Substituted pyridmidines for control of diabetic complications

ABSTRACT

This invention relates to methods of inhibiting sorbitol dehydrogenase, lowering fructose levels, and treating or preventing diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy or diabetic macroangiopathy in a mammal using pyrimidine derivatives of formula (I) wherein R 1 , R 2 , R 3 , R 4  and R 5  are defined as below, and to pharmaceutical compositions containing such derivatives. It also relates to certain novel substituted pyrimidines having the above formula. It also relates to mutual prodrugs of compounds of above formula (I) and aldose reductase inhibiting compounds, and to pharmaceutical compositions comprising a compound of above formula (I) and an aldose reductase inhibitor.

BACKGROUND OF THE INVENTION

This application is a 371 of PCT/US90/06446, filed Jul. 12, 1993,published as WO94/07867, Apr. 14, 1994, which is a continuation in partof U.S. patent application Ser. No. 07/952,222, filed Sep. 28, 1992, nowabandoned.

The present invention relates to novel pyrimidine derivatives and to theuse of such derivatives and related compounds to inhibit sorbitoldehydrogenase, lower fructose levels, or treat or prevent diabeticcomplications such as diabetic neuropathy, diabetic retinopathy,diabetic nephropathy, diabetic microangiopathy and diabeticmacroangiopathy in mammals. This invention also relates topharmaceutical compositions containing such pyrimidine derivatives andrelated compounds.

S. Ao et al., Metabolism, 40, 77-87 (1991) have shown that significantfunctional improvement in the nerves of diabetic rats (based on nerveconduction velocity) occurs when nerve fructose levels arepharmacologically lowered, and that such improvement correlates moreclosely with the lowering of nerve fructose than the lowering of nervesorbitol. Similar results were reported by N. E. Cameron and M. A.Cotter, Diabetic Medicine, 8, Suppl. 1, 35A-36A (1991). In both of thesecases, lowering of nerve fructose was achieved using relatively highdoes of aldose reductase inhibitors, which inhibit the formation ofsorbitol, a precursor of fructose, from glucose via the enzyme aldosereductase.

We have found that pyrimidine derivatives of the formula I, as definedbelow, and their pharmaceutically acceptable salts, lower fructoselevels in the tissues of mammals affected by diabetes (e.g., nerve,kidney and retina tissue) and are useful in the treatment and preventionof the diabetic complications referred to above. These compounds, ortheir metabolites in vivo, are inhibitors of the enzyme sorbitoldehydrogenase, which catalyzes the oxidation of sorbitol to fructose.

SUMMARY OF THE INVENTION

The present invention also relates to the use of substituted pyrimidinesof the formula I, as defined below, to treat or prevent diabeticcomplications in mammals, and to pharmaceutical compositions containingsuch pyrimidines.

Compounds of the formula I are those having the formula ##STR1## whereinR¹ is hydrogen, CF₃, (C₁ -C₆)alkyl, (C₁ -C₆)alkyl--S--(C₁ -C₆)alkyl, (C₁-C₆)alkyl--SO--(C₁ -C₆)alkyl, (C₁ -C₆)alkyl--SO₂ --(C₁ -C₆)alkyl,hydroxy-(C₁ -C₆)alkyl, dihydroxy-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxycarbonyl-(C₁ -C₆)alkyl, aryl selected from phenyl andnaphthyl, aryl-(C₁ -C₆)alkyl wherein the aryl moiety is selected fromphenyl and naphthyl, (C₁ -C₆)alkoxycarbonylaryl wherein the aryl moietyis selected from phenyl and naphthyl, aryl-(C₁ -C₆)alkyl wherein thearyl moiety is selected from phenyl and naphthyl, aryl-(C₁ -C₆)alkyloxywherein the aryl moiety is selected from phenyl and naphthyl, heteroarylselected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl,and benzothienyl; heteroaryl-(C₁ -C₆)alkyl wherein heteroaryl is definedas above, or heteroaryl-(C₁ -C₆)alkyloxy wherein heteroaryl is definedas above, and wherein said aryl and heteroaryl groups, the aryl moietiesof said aryl-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl and aryl-(C₁-C₆)alkyloxy and the heteroaryl moiety of said heteroaryl-(C₁ -C₆)alkylmay optionally be substituted with one or more substituentsindependently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, hydroxy-(C₁ -C₆)alkyl and trifluoromethyl;

or R¹ is a group of the formula ##STR2## wherein the dotted linerepresents an optional double bond, W, Q and Z are independentlyselected from hydrogen, (C₁ -C₆)alkyl and trifluoromethyl, phenyl,furyl, triazolyl, thiazolyl and thienyl, wherein said phenyl, furyl,triazolyl, thiazolyl and thienyl may optionally be substituted with oneor more-substituents independently selected from (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, trifluoromethyl and hydroxy;

or R¹ is a group of the formula ##STR3## wherein R⁶ is hydrogen, (C₁-C₆)alkyl, aryl selected from phenyl and naphthyl, or heteroarylselected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl and benzothienyl,wherein said aryl and heteroaryl groups may optionally be substitutedwith one or more substituents independently selected from chloro, bromo,nitro, trifluoromethyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁-C₆)alkyl and --SO₂ --(C₁ -C₆)alkyl;

or R¹ is a group of the formula ##STR4## wherein R⁷ is aryl selectedfrom phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl,thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl,benzothiazolyl, benzofuranyl, benzothienyl and quinolyl, wherein saidaryl and heteroaryl groups may optionally be substituted with one ormore substituents, preferably with from zero to two substituents,independently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl and trifluoromethyl, and Y is hydrogen, benzyl, acetyl,benzoyl, and selected from phenyl and naphthyl, heteroaryl selected fromfuryl, thienyl, thiazolyl and oxazolyl, wherein said aryl and heteroarylgroups may optionally be substituted with one or more substituentsindependently selected from chloro, bromo, nitro, trifluoromethyl, (C₁-C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl and--SO₂ --(C₁ -C₆)alkyl;

R² and R³ are independently selected from hydrogen, (C₁ -C₆)alkyl,phenyl and phenyl-(C₁ -C₄)alkyl, wherein said phenyl and the phenylmoiety of said phenyl-(C₁ -C₄)alkyl may optionally be substituted withone or more substituents independently selected from (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, chloro, bromo and trifluoromethyl;

or R² and R³ form, together with the nitrogen to which they areattached, a cyclic group selected from azetidino, pyrrolidino,piperidino, piperazino and morpholino, wherein said cyclic group mayoptionally be substituted with from zero to two substituents,independently selected from (C₁ -C₆)alkyl, --CONH₂, --SO₂ NH₂, N-(C₁-C₄)alkylsulfamoyl, N,N-di-(C₁ -C₄)alkylsulfamoyl, (C₁-C₆)alkoxycarbonyl, N,N-di-(C₁ -C₄)alkylcarbamoyl, N-(C₁-C₄)alkylcarbamoyl, N-phenylcarbamoyl, (C₁ -C₆)alkylcarbonyl,phenylcarbonyl, (C₁ -C₆)alkylsulfonyl, (C₁ -C₆)alkylsulfinyl,phenylsulfonyl, heteroarylsulfonyl and heteroarylcarbonyl, wherein theheteroaryl moieties of said heteroarylcarbonyl and heteroarylsulfonylare selected from furyl, thienyl, thiazolyl, and oxazolyl, and whereinthe phenyl moieties of said phenylcarbonyl, N-phenylcarbamoyl,phenylcarbonyl and phenylsulfonyl may optionally be substituted with oneor more substituents independently selected from (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, chloro, bromo, nitro, amino, cyano and trifluoromethyl;

R⁴ is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino, (C₁-C₆)alkyl, (C₁ -C₆)hydroxyalkyl, (C₁ -C₆)alkoxy, phenyl, naphthyl orfuryl, wherein said phenyl, naphthyl and furyl may optionally besubstituted with one or more substituents independently selected fromchloro, bromo, trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁-C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy; and

R⁵ is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, trifluoromethyl, (C₁-C₆)hydroxyalkyl, --S--(C₁ C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, phenyl or furyl, wherein said phenyl and furyl may optionallybe substituted with one or more substituents independently selected fromchloro, bromo, trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₁)alkoxy, --SO--(C₁-C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy.

Several of the substituted pyrimidines of formula I, as well asprocesses for preparing them, are referred to in European PatentApplication 470,616A2, published Feb. 12, 1992 and European PatentApplication 384,370A1, published Aug. 29, 1990. These references areincorporated herein by reference in their entirety.

More specifically, this invention relates to a pharmaceuticalcomposition comprising a sorbitol dehydrogenase inhibiting effectiveamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

This invention also relates to a method of inhibiting the enzymesorbitol dehydrogenase in a mammal, including a human, comprisingadministering to said mammal a sorbitol dehydrogenase inhibitingeffective amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof.

This invention also relates to a pharmaceutical composition comprisingan amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, effective in lowering the level of fructose inone or more of the tissues of a mammal, including a human, that areaffected by diabetes, and a pharmaceutically acceptable carrier.

This invention also relates to a method of lowering the level offructose in one or more of the tissues of a mammal, including a human,that are affected by diabetes, comprising administering to said mammal afructose lowering effective amount of a compound of the formula I, or apharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprisingan mount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, effective in treating or preventing a diabeticcomplication such as diabetic neuropathy, diabetic retinopathy, diabeticnephropathy, or diabetic microangiopathy or macroangiopathy in a mammal,including a human, and a pharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing adiabetic complication such as diabetic neuropathy, diabetic retinopathy,diabetic nephropathy, or diabetic microangiopathy or macroangiopathy ina mammal, including a human, comprising administering to said mammal anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, effective in treating or preventing such complication.

This invention also relates to those compounds of the formula I whereinR¹ is (C₁ -C₆)alkoxycarbonyl-(C₁ -C₆)alkyl, (C₁ -C₆)alkyl--S--(C₁-C₆)alkyl, (C₁ -C₆)alkyl--SO--(C₁ -C₆)alkyl, (C₁ -C₆)alkyl--SO₂ --(C₁-C₆)alkyl, dihydroxy-(C₁ -C₆)alkyl, aryl, heteroaryl, heteroaryl-(C₁-C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl, aryl-(C₁-C₆)alkyloxy or heteroaryl-(C₁ -C₆)alkyloxy, wherein said aryl and thearyl moieties of said aryl-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl,and aryl-(C₁ -C₆)alkyloxy are independently selected from phenyl andnaphthyl, and wherein said heteroaryl and the heteroaryl moieties ofsaid heteroaryl-(C₁ -C₆)alkyl and heteroaryl-(C₁ -C₆)alkyloxy areindependently selected from wherein the aryl moiety is selected fromphenyl and naphthyl, heteroaryl selected from pyridyl, furyl,tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl,oxazolyl and benzothiazolyl, and wherein said aryl and heteroaryl andthe aryl and heteroaryl moieties of said heteroaryl-(C₁ -C₆)alkyl,aryl-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl, aryl-(C₁ -C₆)alkoxy andheteroaryl-(C₁ -C₆)alkyloxy may optionally be substituted with one ormore substituents, preferably with one or two substituents,independently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, hydroxy-(C₁ -C₆)alkyl and trifluoromethyl;

or R¹ is a group of the formula ##STR5## wherein the dotted linerepresents an optional double bond, W, Q and Z are independentlyselected from hydrogen, (C₁ -C₆)alkyl and trifluoromethyl, phenyl,furyl, triazolyl, thiazolyl and thienyl, wherein said phenyl, furyl,triazolyl, thiazolyl and thienyl may optionally be substituted with oneor more substituents, preferably with from zero to two substituents,independently selected from (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy,trifluoromethyl and hydroxy;

or R¹ is a group of the formula ##STR6## wherein R⁶ is hydrogen, (C₁-C₆)alkyl, aryl selected from phenyl and naphthyl, or heteroarylselected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl and benzothienyl,wherein said aryl and heteroaryl groups may optionally be substitutedwith one or more substituents, preferably with from zero to twosubstituents, independently selected from chloro, bromo, nitro,trifluoromethyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyland --SO₂ --(C₁ -C₆)alkyl;

or R¹ is a group of the formula ##STR7## wherein R⁷ is aryl selectedfrom phenyl and naphthyl, or heteroaryl selected from pyridyl, furyl,thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl,benzothiazolyl, benzofuranyl, benzothienyl and quinolyl, wherein saidaryl and heteroaryl groups may optionally be substituted with one ormore substituents, preferably with from zero to two substituents,independently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl and trifluoromethyl, and Y is hydrogen, benzyl, acetyl,benzoyl, aryl selected from phenyl and naphthyl, heteroaryl selectedfrom furyl, thienyl, thiazolyl and oxazolyl, wherein said aryl andheteroaryl groups may optionally be substituted with one or moresubstituents, preferably with from zero to two substituents,independently selected from chloro, bromo, nitro, trifluoromethyl, (C₁-C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl and--SO₂ --(C₁ -C₆)alkyl.

These novel compounds are hereinafter referred to, collectively, ascompounds of the formula IA. This invention also relates to thepharmaceutically acceptable acid addition and base salts of the novelcompounds of formula IA.

This invention also relates to mutual prodrugs of a compound of theformula I and an aldose reductase inhibiting compound.

This invention also relates to compounds of the formula ##STR8## whereinR²⁵ is ##STR9## and R²⁶ is aryl selected from phenyl and naphthyl,wherein said aryl may optionally be substituted with one or moresubstituents, preferably with one or two substituents, independentlyselected from chloro, bromo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁-C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl, hydroxy-(C₁-C₆)alkyl and trifluoromethyl;

R² and R³ are independently selected from hydrogen, (C₁ -C₆)alkyl,phenyl and phenyl-(C₁ -C₄)alkyl, wherein said phenyl and the phenylmoiety of said phenyl-(C₁ -C₄)alkyl may optionally be substituted withone or more substituents, preferably with from zero to two substituents,independently selected from (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, chloro, bromoand trifluoromethyl;

or R² and R³ form, together with the nitrogen to which they areattached, a cyclic group selected from azetidino, pyrrolidino,piperidino, piperazino and morpholino, wherein said cyclic group mayoptionally be substituted with from zero to two substituentsindependently selected from (C₁ -C₆)alkyl, --CONH₂, --SO₂ NH₂, N-(C₁-C₄)alkylsulfamoyl, N,N-di-(C₁ -C₄)alkylsulfamoyl, (C₁-C₆)alkoxycarbonyl, N,N-di-(C₁ -C₄)alkylcarbamoyl, N-(C₁-C₄)-alkylcarbamoyl, N-phenylcarbamoyl, (C₁ -C₆)alkylcarbonyl,phenylcarbonyl, (C₁ -C₆)alkylsulfonyl, (C₁ -C₆)alkylsulfinyl,phenylsulfonyl, heteroarylsulfonyl and heteroarylcarbonyl, wherein theheteroaryl moieties of said heteroarylcarbonyl and heteroarylsulfonylare selected from furyl, thienyl, thiazolyl and oxazolyl, and whereinthe phenyl moieties of said phenylcarbonyl, N-phenylcarbamoyl,phenylcarbonyl and phenylsulfonyl may optionally be substituted with oneor more substituents, preferably with from zero to two substituents,independently selected from (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, chloro,bromo, nitro, amino, cyano and trifluoromethyl;

R⁴ is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino, (C₁-C₆)alkyl, (C₁ -C₆)hydroxyalkyl, (C₁ -C₆)alkoxy, phenyl, naphthyl orfuryl, wherein said phenyl, naphthyl and furyl may optionally besubstituted with one or more substituents, preferably with from zero totwo substituents, independently selected from chloro, bromo,trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl,--SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy;

R⁵ is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, trifluoromethyl, (C₁-C₆)hydroxyalkyl, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, phenyl or furyl, wherein said phenyl and furyl may optionallybe substituted with one or more substituents, preferably with from zeroto two substituents, independently selected from chloro, bromo,trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl,--SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy;

R⁸ is hydrogen or R⁷ ;

R⁷ is aryl selected from phenyl and naphthyl, or heteroaryl selectedfrom pyridyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl, benzothienyl andquinolyl, wherein said aryl and heteroaryl groups may optionally besubstituted with one or more substituents, preferably with from zero totwo substituents, independently selected from chloro, bromo, (C₁-C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl,--SO₂ --(C₁ -C₆)alkyl and trifluoromethyl, and Y is hydrogen, benzyl,acetyl, benzoyl, aryl selected from phenyl and naphthyl, or heteroarylselected from furyl, thienyl, thiazolyl and oxazolyl, wherein said aryland heteroaryl groups may optionally be substituted with one or moresubstituents, preferably with from zero to two substituents,independently selected from chloro, bromo, nitro, trifluoromethyl, (C₁-C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl and--SO₂ --(C₁ -C₆)alkyl;

Y² is ##STR10## or Y² is absent (i.e., the carbon to which R⁸ isattached is directly bonded to ##STR11##

Y⁴ is hydrogen or (C₁ -C₆)alkyl; and

Y³ is selected from the following groups: ##STR12## wherein A is CH₂,CH₂ CH₂, CH(CH₃) or ##STR13##

B is oxygen or sulfur;

R⁹ is selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl,benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl,oxazolopyridin-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, and5-phenyl-1,2,4-oxadiazol-3-yl, and R⁹ may optionally be substituted withfrom one to three substituents independently selected from fluorine,chlorine, bromine, methyl, methylthio, methoxy, hydroxy andtrifluoromethyl;

R¹⁰ and R¹¹ are independently selected from hydrogen, fluorine,chlorine, bromine, (C₁ -C₄)alkyl, (C₁ -C₄)alkylthio, (C₁ -C₄)alkoxy andtrifluoromethyl;

or R¹⁰ and R¹¹ together, with the carbons to which they are attached,form a group of the formula ##STR14## wherein p is 1 or 2; D and E areindependently selected from --CH₂ --, oxygen and sulfur, except that Dand E cannot both be oxygen and cannot both be sulfur; R¹² and R¹³ areindependently selected from hydrogen, fluorine, chlorine, bromine, (C₁-C₄)alkyl, (C₁ -C₄)alkylthio, (C₁ -C₄)alkoxy and trifluoromethyl; and Fand G are independently selected from --CH-- and nitrogen;

R¹² and R¹³ are independently selected from hydrogen, fluorine,chlorine, bromine, (C₁ -C₄)alkyl, (C₁ -C₄)alkylthio, (C₁ -C₄)alkoxy andtrifluoromethyl;

K is oxygen, sulfur, SO or SO₂ ;

R¹⁴ is hydrogen, fluoro, chloro, bromo, methyl, nitro, cyano,methanesulfonyl or benzoyl;

R¹⁵ is hydrogen, fluoro, chloro, bromo, carboxy, (C₁ -C₃)alkyl, (C₁-C₃)alkoxy or benzyloxy;

R¹⁶ is hydrogen, fluoro, chloro, bromo or (C₁ -C₃)alkyl;

or R¹⁵ and R¹⁶, together with the carbon atoms to which they areattached, form a 7,8-benzo ring;

R¹⁷ is (C₁ -C₄)alkyl, trifluoromethyl or (CH₂)_(n) Ar, wherein n is 0, 1or 2 and Ar is phenyl optionally substituted with one or twosubstituents independently selected from methoxy, fluoro, chloro andbromo;

R¹⁸ is hydrogen, methyl or ethyl;

or R¹⁷ and R¹⁸, together with the carbon to which they are attached,form a saturated 4 or 5 membered carbocyclic spiro ring; and

R¹⁹ is hydrogen or methyl;

with the proviso that: (a) when K is other than oxygen, R¹⁴ is fluoro,chloro, cyano or nitro, and R¹⁵ and R¹⁶ do not form a 7,8-benzo ring;and (b) when K is other than oxygen or R¹⁷ is other than methyl, ethylor trifluoromethyl, both R¹⁸ and R¹⁹ are hydrogen; and (c) when Y³ is agroup of the formula XIVA, R⁹ is benzothiazol-2-yl or substitutedbenzothiazol-2-yl;

and the pharmaceutically acceptable salts of such compounds.

Compounds of the formula ##STR15## wherein Y³ is one of the above groupsVII to XIV are known aldose reductase inhibitors. Compounds of theformula VI wherein R²⁵ is ##STR16## are conjugates and mutual prodrugsof such aldose reductase inhibitors and the pharmaceutically activecompounds of the formula I wherein R¹ is --CH₂ OH, --CHR⁷ OH orhydroxy-(C₁ -C₆)alkyl. As mutual prodrugs, they are expected to releasein vivo both pharmaceutically active agents--a compound of the formula Iwherein R¹ is --CH₂ OH, --CHR⁷ OH or hydroxy-(C₁ -C₆)alkyl and an aldosereductase inhibitor of the formula ##STR17##

Compounds of the formula O₂ N--CH₂ --SO₂ --R²⁶ --R²⁶ --NH₂, wherein R²⁶is defined as above, are also known aldose reductase inhibitors.Compounds of the formula VI wherein R²⁵ is ##STR18## are conjugates andmutual prodrugs of such aldose reductase inhibitors and thepharmaceutically active compounds of the formula I wherein R¹ is --CH₂OH, --CHR⁷ OH or hydroxy-(C₁ -C₆)alkyl. As mutual prodrugs, they areexpected to release in vivo both pharmaceutically active agents--acompound of the formula I wherein R¹ is --CH₂ OH, --CHR⁷ OH orhydroxy-(C₁ -C₆)alkyl and an aldose reductase inhibitor of the formulaO₂ N--CH₂ --SO₂ --R²⁶ --NH₂.

Preferred embodiments of this invention include those compounds of theformula VI, and pharmaceutically acceptable salts thereof, wherein R²⁵is ##STR19## is not absent and: (a) Y³ is a group of the formula VII, R⁹is phenyl, substituted phenyl, benzothiazol-2-yl or benzoxazol-2-yl, Ais --CH₂ --, and R¹⁰ and R¹¹ are either both methyl or they form,together with the carbons to which they are attached, a group of theformula ##STR20## (b) Y³ is a group of the formula VIII, R⁹ is phenyl,substituted phenyl, benzothiazol-2-yl or benzoxazol-2-yl, A is --CH₂ --,and R¹² and R¹³ are independently selected from bromo and chloro; (c) Y³is a group of the formula IX and each of R¹² and R¹³ is hydrogen; (d) Y³is a group of the formula X and R¹² and R¹³ are independently selectedfrom (C₁ -C₆)alkoxy and trifluoromethyl; (e) Y³ is a group of theformula XI and R¹² and R¹³ are independently selected from (C₁-C₆)alkyl; (f) Y³ is a group of the formula XII, R⁹ is phenyl,substituted phenyl or benzothiazol-2-yl, A is --CH₂ -- and R¹² and R¹³are independently selected from chloro and bromo; or (g) Y³ is a groupof the formula XIII, each of R¹⁴ and R¹⁹ is hydrogen, each of R¹⁷ andR¹⁸ is methyl, R¹⁵ is 6-chloro or 6-fluoro and R¹⁶ is 7-chloro or7-fluoro.

Preferred embodiments of this invention also include those compounds ofthe formula VI that are mutual prodrugs of a compound of the formula Iand an aldose reductase inhibitor of the formula ##STR21## wherein suchaldose reductase inhibitor is selected from:

3,4-dihydro-4-oxo-3-(5-trifluoromethyl)-2-benzothiazolyl!-methyl!-1-phthalazineacetic acid;

3,4-dihydro-4-oxo-3-(5,7-difluoro)-2-benzothiazolyl!-methyl!-1-phthalazineacetic acid;

3,4-dihydro-4-oxo-3-(5,7-dichloro)-2-benzothiazolyl!-methyl!-1-phthalazineacetic acid;

2-4-(4,5,7-trifluorobenzothiazol-2-yl)methyl-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl!aceticacid;

4,5-dimethyl-6-oxo-1-(5-trifluoromethyl-benzothiazolylmethyl)-1,6-dihydro-pyridazin-3-yl!-aceticacid;

4,5-dimethyl-6-oxo-1-(5,7-difluoro-benzothiazolylmethyl)-1,6-dihydro-pyridazin-3-yl!-aceticacid;

4,5-dimethyl-6-oxo-1-(5,7-dichlorobenzothiazol-2-ylmethyl)-1,6-dihydro-pyridazin-3-yl!-aceticacid;

4-oxo-3(5-trifluoromethyl)-benzothiazol-2-ylmethyl!3,4,5,6,7,8-hexahydro-phthalazin-1-yl!-aceticacid;

4-oxo-3-(5,7-difluoro)-benzothiazol-2-ylmethyl!-3,4,5,6,7,8-hexahydro-phthalazin-1-yl!-aceticacid;

4-oxo-3-(5,7-dichloro)-benzothiazol-2-ylmethyl!-3,4,5,6,7,8-hexahydro-phthalazin-1-yl!-aceticacid;

N-5-trifluoromethyl)-6-methoxy-1-naphthalenyl!thioxomethyl!-N-methylglycine;

3,4-dihydro-4-oxo-3-(4-bromo-2-fluorobenzyl)-1-phthalazineacetic acid;

(Z)-3-(carboxymethyl- (2E)-methylphenylpropenylidene!-rhodanine;

2-3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxo-1-quinazolinyl!-aceticacid;

2R,4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid;

2R,4R-7-chloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid; and

3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid.

This invention also relates to a pharmaceutical composition comprising:(a) an amount of a mutual prodrug of a compound of the formula I and analdose reductase inhibiting compound, or a pharmaceutically acceptablesalt of such a prodrug, effective in lowering the level of fructose inone or more of the tissues of a mammal, including a human, that areaffected by diabetes; and (b) a pharmaceutically acceptable carrier.

This invention also relates to a method of lowering the level offructose in one or more of the tissues of a mammal, including a human,that are affected by diabetes, comprising administering to said mammal afructose lowering effective agent of a mutual prodrug of a compound ofthe formula I and an aldose reductase inhibiting compound, or apharmaceutically acceptable salt of such a prodrug.

This invention also relates to a pharmaceutical composition comprising:(a) an amount of a mutual prodrug of a compound of the formula I and analdose reductase inhibiting compound, or a pharmaceutically acceptablesalt of such a prodrug, effective in treating or preventing a diabeticcomplication such as diabetic neuropathy, diabetic retinopathy, diabeticnephropathy, or diabetic microangiopathy or macroangiopathy in a mammal,including a human; and (b) a pharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing adiabetic complication such as diabetic neuropathy, diabetic retinopathy,diabetic nephropathy, or diabetic microangiopathy or macroangiopathy ina mammal, including a human, comprising administering to said mammal anamount of a mutual prodrug of a compound of the formula I and an aldosereductase inhibiting compound, or a pharmaceutically acceptable salt ofsuch a prodrug, effective in treating or preventing such complication.

This invention relates to a pharmaceutical composition comprising anamount of a compound of the formula VI, or a pharmaceutically acceptablesalt thereof, effective in lowering the level of fructose in one or moreof the tissues of a mammal, including a human, that are affected bydiabetes, and a pharmaceutically acceptable carrier.

This invention also relates to a method of lowering the level offructose in one or more of the tissues of a mammal, including a human,that are affected by diabetes, comprising administering to said mammal afructose lowering effective amount of a compound of the formula VI, or apharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprisingan mount of a compound of the formula VI, or a pharmaceuticallyacceptable salt thereof, effective in treating or preventing a diabeticcomplication such as diabetic neuropathy, diabetic retinopathy, diabeticnephropathy, or diabetic microangiopathy or macroangiopathy in a mammal,including a human, and a pharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing adiabetic complication such as diabetic neuropathy, diabetic retinopathy,diabetic nephropathy, or diabetic microangiopathy or macroangiopathy ina mammal, including a human, comprising administering to said mammal anamount of a compound of the formula VI, or a pharmaceutically acceptablesalt thereof, effective in treating or preventing such complication.

Compounds of the formulae XV-XIX, which are defined below, and theirpharmaceutically acceptable salts, are also known compounds that exhibitactivity as aldose reductase inhibitors. These compounds have thefollowing structures: ##STR22## wherein L is oxygen, CH₂ sulfur or##STR23##

J is hydrogen, methyl or --CNH₂ ;

G is CH or N;

R²⁰ and R²¹ are independently selected from hydrogen, fluorine,chlorine, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁-C₆)alkyl or --SO₂ --(C₁ -C₆)alkyl;

M is phenyl, naphthyl or a heteroaryl group selected from furan,morpholine, pyrrolidine, tetmhydroisoquinoline, thiophene, thiazole,oxazole, benzofuran, benzothiophene, benzothiazole, benzoxazole andindole, wherein said phenyl, naphthyl and heteroaryl groups mayoptionally be substituted with up to three substituents independentlyselected from chloro, fluoro, bromo, cyano, nitro, hydroxy, carboxy,amino (C₁ -C₆)alkylamino, (C₁ -C₆)dialkylamino, (C₁ -C₆)alkanoylamino,(C₁ -C₆)alkanoyl, (C₁ -C₆)alkyl, (C₂ -C₆)alkenyl, (C₃ -C₆)alkenyloxy,fluoro-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, fluoro-(C₁ -C₄)alkoxy, (C₁-C₆)hydroxyalkyl, carbamoyl, (C₁ -C₇)alkylcarbamoyl, (C₁-C₇)dialkylcarbamoyl, sulfamoyl, (C₁ -C₆)alkysulfamoyl, (C₁-C₆)dialkylsulfamoyl, (C₁ -C₆)alkoxycarbonyl ,(C₁ -C₄)alkylenedioxy, (C₁-C₆)alkanesulfonamido , --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂--(C₁ -C₆)alkyl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl,benzamido, and benzenesulfonamido, and wherein said phenyl and thephenyl moieties of said phenoxy, benzyloxy, benzyloxycarbonyl, benzamidoand benzenesulfonamido may optionally be substituted with a substituentselected from chlorine, fluorine, (C₁ -C₄)alkyl (C₁ -C₄)alkoxy and##STR24## wherein Y⁵ is oxygen or sulfur, or Y⁵ is absent (i.e., thephenyl ring is bonded to the carbon to which R²² and R²³ are attached),and R²² and R²³ are independently selected from hydrogen and (C₁-C₄)alkyl, and the phenyl moiety to which the --NHCOC(R²²)(R²³)--Y⁵ --sidechain is attached may optionally be substituted with from one tothree substituents independently selected from hydrogen, halo,trifluoromethyl, nitro, cyano, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy and (C₁-C₄)alkanoyl, or any adjacent pair of substituents may form, togetherwith the carbons to which they are attached, a benzo ring which mayoptionally be substituted with a substituent independently selected fromhalo, (C₁ -C₄)alkyl and (C₁ -C₄)alkoxy;

with the proviso that: (a) when J is ##STR25## G is CH and L is oxygen;and (b) M is not 2-carboxyphenyl.

This invention also relates to a pharmaceutical composition comprising:(a) an amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, that is effective in lowering the level offructose in one or more of the tissues of a mammal, including a human,that are affected by diabetics; (b) an amount of an aldose reductaseinhibiting compound, or a pharmaceutically acceptable salt thereof, thatis effective in lowering the level of fructose in one or more of thetissues of a mammal, including a human, that are affected by diabetesand (c) a pharmaceutically acceptable carrier.

This invention also relates to a method of lowering the level offructose in one or more of the tissues of a mammal, including a human,that are affected by diabetes, comprising administering to said mammal afructose lowering effective amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, in combination with a fructoselowering effective amount of an aldose reductase inhibiting compound, ora pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprising:(a) an amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, effective in treating or preventing a diabeticcomplication such as diabetic neuropathy, diabetic retinopathy, diabeticnephropathy, or diabetic microangiopathy or macroangiopathy in a mammal,including a human; (b) an amount of an aldose reductase inhibitingcompound, or a pharmaceutically acceptable salt thereof, effective intreating or preventing a diabetic complication such as diabeticneuropathy, diabetic retinopathy, diabetic nephropathy or diabeticmicroangiopathy or macroangiopathy in a mammal, including a human; and(c) a pharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing adiabetic complication such as diabetic neuropathy, diabetic retinopathy,diabetic nephropathy, or diabetic microangiopathy or macroangiopathy ina mammal, including a human, comprising administering to said mammal anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, effective in treating or preventing such complication, incombination with an amount of an aldose reductase inhibiting compound,or a pharmaceutically acceptable salt thereof, effective in treating orpreventing such complication.

This invention also relates to a pharmaceutical composition comprising:(a) an amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, that is effective in lowering the level offructose in one or more of the tissues of a mammal, including a human,that are affected by diabetics; (b) an amount of a compound of theformula XV, XVI, XVII, XVIII or XIX, or a pharmaceutically acceptablesalt thereof, that is effective in lowering the level of fructose in oneor more of the tissues of a mammal, including a human, that are affectedby diabetes and (c) a pharmaceutically acceptable carrier.

This invention also relates to a method of lowering the level offructose in one or more of the tissues of a mammal, including a human,that are affected by diabetes, comprising administering to said mammal afructose lowering effective amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, in combination with a fructoselowering effective amount of a compound of the formula XV, XVI, XVII,XVIII or XIX, or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprising:(a) an amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, effective in treating or preventing a diabeticcomplication such as diabetic neuropathy, diabetic retinopathy, diabeticnephropathy, or diabetic microangiopathy or macroangiopathy in a mammal,including a human; (b) an amount of a compound of the formula XV, XVI,XVII, XVIII or XIX, or a pharmaceutically acceptable salt thereof,effective in treating or preventing a diabetic complication such asdiabetic neuropathy, diabetic retinopathy, diabetic nephropathy ordiabetic microangiopathy or macroangiopathy in a mammal, including ahuman; and (c) a pharmaceutically acceptable carrier.

This invention also relates to a method of treating or preventing adiabetic complication such as diabetic neuropathy, diabetic retinopathy,diabetic nephropathy, or diabetic microangiopathy or macroangiopathy ina mammal, including a human, comprising administering to said mammal anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, effective in treating or preventing such complication, incombination with an amount of a compound of the formula XV, XVI, XVII,XVIII or XIX, or a pharmaceutically acceptable salt thereof, effectivein treating or preventing such complication.

Preferred embodiments of this invention include those pharmaceuticalcompositions and methods set forth above, wherein the compound offormula I, or pharmaceutically acceptable salt thereof, that is employedis a compound wherein R¹ is (C₁ -C₆)hydroxyalkyl, (C₁ -C₆)alkoxy,imidazolyl, furyl, pyrazolyl, tetrahydrofuryl, thienyl or triazolyl, orR¹ is Y--O--CH--R⁷ wherein R⁷ is benzothiazolyl, furyl, imidazolyl,pyrazolyl, thienyl, triazolyl, (C₁ -C₆)alkyl or trifluoromethyl, and Yis hydrogen or (C₁ -C₆)alkyl, and R² and R³ form, together with thenitrogen to which they are attached, a group of the formula ##STR26##wherein X is carbon or --SO-- and R²⁴ is amino, (C₁ -C₆)alkylamino,di-(C₁ -C₆)alkylamino or pyridyl.

Particularly preferred embodiments of this invention are thosepharmaceutical compositions and methods referred to above, wherein thecompound of formula I, or pharmaceutically acceptable salt thereof, thatis employed is a compound wherein R¹ is (C₁ -C₆)alkyl, (C₁-C₆)hydroxyalkyl, (C₁ -C₆)alkoxy, furyl, triazolyl, or tetrahydrofuryl,or R¹ is ##STR27## wherein R⁷ is benzothiazolyl, furyl, thiazolyl,thienyl or trifluoromethyl, and Y is hydrogen or (C₁ -C₆)alkyl, each ofR⁴ and R⁵ is hydrogen, and R² and R³, together with the nitrogen towhich they are attached, form a group of the formula ##STR28## whereinR²⁷ and R²⁸ are, independently, methyl or ethyl.

Other particularly preferred embodiments of this invention are thosepharmaceutical compositions and methods referred to above, wherein thecompound of formula I, or pharmaceutically acceptable salt thereof, thatis employed is a compound wherein R¹ is (C₁ -C₆)hydroxyalkyl, furyl ortriazolyl, or R¹ is ##STR29## wherein R⁷ is furyl, thienyl ortrifluoromethyl and Y is hydrogen, each of R⁴ and R⁵ is hydrogen, and R²and R³, together with the nitrogen to which they are attached, form agroup of the formula ##STR30## wherein R²⁷ and R²⁸ are, independently,hydrogen, methyl or ethyl.

Preferred embodiments of this invention also include the pharmaceuticalcompositions and methods set forth above, wherein the compound offormula I, or pharmaceutically acceptable salt thereof, that is employedis selected from:

4- 4-(N-methylsulfamoyl)-piperazino!-2-methylpyrimidine;

4- 4-(N-sulfamoyl)-piperazino!-2-methylpyrimidine;

4- 4-(N,N-dimethylsulfamoyl)-piperazino!-2-methylpyrimidine;

4- 4-(N-methylsulfamoyl)-piperizino!-2-hydroxymethylpyrimidine;

4- 4-(N-sulfamoyl)-piperizino!-2-hydroxymethylpyrimidine; and

4- 4-(N,N-dimethylsulfamoyl)-piperizino!-2-hydroxymethylpyrimidine.

Preferred embodiments of this invention also include thosepharmaceutical compositions and methods set forth above that comprise oremploy a composition comprising an aldose reductase inhibitor selectedfrom:

(4-amino-2,6-dimethylphylsulfonyl)nitromethane;

N,N-diisopropyl-N'- 3,5-dimethyl-4-(nitromethylsulfonyl)phenyl!oxamide;

N- 3,5-dimethyl-4-(nitromethylsulfonyl)phenyl!-2-(piperidino)glyoxamide;

2,6-dimethyl-4-(phenylacetamido)phenylsulfonyl!nitromethane;

2,6-dimethyl-4-(2-phenoxyacetamido)phenylsulfonyl!nitromethane;

2,6-dimethyl-4-(2-(3-methylphenoxyacetamido)phenyl)sulfonyl!nitromethane;

2,6-dimethyl-4-(2-(3-chlorophenoxyacetamido)phenyl)sulfonyl!nitromethane;

2,6-dimethyl-1-((2,4,6-trimethylphenyl)acetamido)phenylsulfonyl!nitromethane;

2,6-dimethyl-4-((2-methylphenyl)acetamido)phenylsulfonyl nitromethane;

2,6-dimethyl-4-((2-fluorophenyl)acetamido)phenylsulfonyl nitromethane;

2-(nitromethylsulfonyl)thiophene;

2-chloro-5-(nitromethylsulfonyl)thiophene;

N-(nitromethylsulfonyl)morpholine;

N-(nitromethylsulfonyl)piperidine;

N-(nitromethylsulfonyl)indoline;

d-6-fluoro-spiro(chroman-4,4'-imidazolidine)-2',5'-dione;

2-fluoro-spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione;

2,7-difluoro-spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione;

2,7'-difluoro-5-methoxy-spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione;

7-fluoro-spiro (5H-indenol 1,2-b!pyridine-5,3'-pyrrolidine)2,5'-dione;

d-cis-6'-chloro-2',3'-dihydro-2'-methyl-spiro-(imidazolidine-4,4'-4'H-pyrano(2,3-b)pyridine)-2,5-dione;

spiroimidazolidine-4,5'(6H)-quinoline!2,5-dione-3'-chloro-7',8'-dihydro-7'-methyl-,(5'S-cis); and

(2S,4S)-6-fluoro-2',5'-dioxospiro(chroman-4,4'-imidazolidine)-2-carboxamide.

"A sorbitol dehydrogenase inhibiting effective amount of a compound ofthe formula I, or a pharmaceutically acceptable salt thereof," as usedherein, refers to an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that exhibits sorbitoldehydrogenase inhibiting activity, or an amount of such compound or saltthat yields a metabolite in vivo that exhibits sorbitol dehydrogenaseinhibiting activity.

The term "alkyl", as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term "alkoxy", as used herein, includes O-alkyl groups wherein"alkyl" is defined as above.

The term "one or more substituents," as used herein, includes from oneto the maximum number of substituents possible based on the number ofavailable bonding sites.

The acids that may be used to prepare pharmaceutically acceptable acidaddition salts of those compounds of formulae I and VI that are basic innature are those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzene-sulfonate, p-toluenesulfonate and pamoate i.e.,1,1'-methylene-bis-(2-hydroxy-3-naphthoate)!salts. The chemical basesthat may be used as reagents to prepare pharmaceutically acceptable basesalts of those compounds of formulae I and VI that are acidic in natureare those that form non-toxic base salts with such compounds. Suchnon-toxic base salts include, but are not limited to those derived fromsuch pharmacologically acceptable cations such as alkali metal cations(e.g., potassium and sodium) and alkaline earth metal cations (e.g.,calcium and magnesium), ammonium or water-soluble amine addition saltssuch as N-methylglucamine-(meglumine), and the lower alkanolammonium andother base salts of pharmaceutically acceptable organic amines.

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the dose dependent lowering of erythrocyte fructoseby 4- 4-(N,N-dimethylsulfamoyl)piperizino!-2-methylpyrimidine (referredto in FIG. 1 as "Compound 1") in diabetic rats.

FIG. 2 illustrates the dose dependent elevation of erythrocyte sorbitolby 4- 4-(N,N-dimethylsulfamoyl)piperizino!-2-methylpyrimidine (referredto in FIG. 2 as "Compound 1") in diabetic rats.

FIG. 3 illustrates the dose dependent lowering of nerve fructose by 4-4-(N,N-dimethylsulfamoyl)piperizino!-2-methylpyrimidine (referred to inFIG. 3 as "Compound 1") in diabetic rats.

FIG. 4 illustrates the dose dependent elevation of nerve sorbitol by 4-4-(N,N-dimethylsulfamoyl)piperizino!-2-methylpyrimidine (referred to inFIG. 4 as "Compound 1") in diabetic rats.

FIG. 5 illustrates the dose dependent in vitro inhibition of sorbitoldehydrogenase by sera from rats dosed with 4-4-(N,N-dimethylsulfamoyl)piperizino!-2-methylpyrimidine (referred to inFIG. 5 as "Compound 1").

FIG. 6 illustrates the dose dependent in vitro inhibition of sorbitoldehydrogenase by urine from rats dosed with 4-4-(N,N-dimethylsulfamoyl)piperizino!-2-methylpyrimidine (referred to inFIG. 6 as "Compound 1").

DETAILED DESCRIPTION OF THE INVENTION

Many of the substituted pyrimidines of the formula I are knowncompounds. These may be prepared from commercially available or knownstarting materials by the procedures set forth in European PatentApplication 47061 6A2, published Feb. 12, 1992 and European PatentApplication 384,370A1, published Aug. 29, 1990.

Compounds of the formula XV may be prepared as described in U.S. Pat.No. 4,130,714, which issued to Reinhard Sarges on Dec. 19, 1978, U.S.Pat. No. 5,066,659 which issued to Christopher A. Lipinski on Nov. 19,1991, U.S. Pat. No. 4,566,670, which issued to Christopher A. Lipinskion Dec. 3, 1985, U.S. Pat. No. 4,980,357, which issued to Goldstein etal. on Dec. 25, 1990, U.S. Pat. No. 4,540,704, which issued to Ueda etal. on Sep. 10, 1985, and U.S. Pat. No. 4,985,573, which issued toKurono et al. on Jan. 15, 1991. Compounds of the formula XVI may beprepared as described in U.S. Pat. Nos. 4,436,745 and 4,438,272, whichissued to Billie M. York, Jr. on Mar. 13, 1984 and Mar. 20, 1984,respectively. All of the foregoing documents are incorporated herein byreference in their entirety.

Compounds of the formulae VII and VIII may be prepared as described inU.S. Pat. No. 5,039,672, which issued to Eggler et al. on Aug. 13, 1991.Compounds of the formula XIX may be prepared as described in EuropeanPatent Applications EP 304190, EP 408713, EP 409449, EP 469887 and EP469888, which were published, respectively, on Feb. 22, 1989, Jan. 23,1991, Jan. 30, 1991, Feb. 5, 1992 and Feb. 5, 1992, U.S. Pat. No.5,110,808, which issued to Brittain et al. on May 5, 1992, U.S. Pat. No.5,102,905, which issued to Brown et al. on Apr. 7, 1992, and U.S. Pat.No. 5,096,918, which issued to Keith B. Mallion on Mar. 17, 1992. All ofthe foregoing documents are incorporated herein by reference in theirentirety.

Compounds of the formula ##STR31## wherein Y³ is a group of the formulaVII, as defined above, may be prepared as described in U.S. Pat. No.4,251,528, which issued to Brittain et al. on Feb. 17, 1981, U.S. Pat.No. 4,996,204, which issued to Mylari et al. on Feb. 26, 1991, U.S. Pat.No. 4,939,140, which issued to Larsen et al. on Jul. 3, 1990, PCT PatentApplication PCT/US 92/01603, which was filed on Mar. 9, 1992, EuropeanPatent Application EP 436307, which was published on Jul. 10, 1991, andFrench Patent Application FR 2647676A1, which was published on Dec. 7,1990. Compounds of the formula ##STR32## wherein Y³ is a group of theformula IX, as defined above, may be prepared as described in U.S. Pat.No. 4,464,382, U.S. Pat. No. 4,791,126 and U.S. Pat. No. 4,831,045,which issued to Tanouchi et al. on, respectively, Aug. 7, 1984, Dec. 13,1988 and May 16, 1989. All of the foregoing documents are incorporatedherein by reference in their entirety.

Compounds of the formula ##STR33## wherein Y³ is a group of the formulaX, as defined above, may be prepared as described in U.S. Pat. No.4,391,825, which issued to Bellini et al. on Jul. 5, 1983, and in U.S.Pat. No. 4,568,693, U.S. Pat. No. 4,600,724 and U.S. Pat. No. 4,705,882,which issued to Sestanj et al. on, respectively, Feb. 4, 1986, Jul. 15,1986 and Nov. 10, 1987. Compounds of the formula ##STR34## wherein Y³ isa group of the formula XI, as defined above, may be prepared asdescribed in U.S. Pat. No. 4,771,050, which issued to Meguro et al. onSep. 13, 1988. Compounds of the formula ##STR35## wherein Y³ is a groupof the formula XII, as defined above, may be prepared as described byBillon et al. Eur. J. Med. Chem., 25, 121 (1990). All of the foregoingdocuments are incorporated herein by reference in their entirety.

Compounds of the formula ##STR36## wherein Y³ is a group of the formulaXIII, as defined above, may be prepared as described in U.S. Pat. No.4,883,410, which issued to Christopher A. Lipinski on Aug. 1, 1989.Compounds of the formula ##STR37## wherein Y³ is a group of the formulaXIV, as defined above, may be prepared as described in European PatentApplication 325375, which was published on Jul. 26, 1989. Compounds ofthe formula ##STR38## wherein Y³ is a group of the formula XIVA, asdefined above, may be prepared as described in European PatentApplication 492667A1, which was published on Jul. 1, 1992. All of theforegoing documents are incorporated herein by reference in theirentirety.

Methods of preparing the various compounds and compositions of thisinvention are described below. Unless otherwise noted, in the reactionschemes and discussion that follow, R¹ through R²⁸, Q, W, Y, Y², Y³, Y⁴,Y⁵, A, B, D, E, G, J, L, and M are defined as above.

Reaction schemes 1-3 below illustrate methods of preparing the novelcompounds of the formula IA. ##STR39##

Referring to scheme 1, compounds of the formula IA wherein R¹ is##STR40## and R⁶ is hydrogen may be prepared by oxidizing thecorresponding compounds wherein R¹ is hydroxymethyl (--CH₂ OH).Oxidizing agents that may be used include chromic acid, silver oxide andactivated manganese dioxide, with activated manganese dioxide beingpreferred. When chromic acid is used, the preferred solvent is water oran aqueous (C₃ -C₆)alkyl ketone (e.g., acetone) and the reactiontemperature, which can range from about -78° C. to about 25° C., ispreferably from about -10° C. to about 0° C. When silver oxide oractivated manganese dioxide is used, the solvent is preferably ahalocarbon solvent such as chloroform or methylene chloride, and thereaction temperature, which can range from about 0° C. to about 100° C.,is preferably between about 20° C. and the reflux temperature of thesolvent.

Compounds of the formula IA wherein R¹ is ##STR41## and R⁶ is other thanhydrogen may be prepared by first reacting the corresponding compoundwherein R¹ is formyl (CHO) with an organolithium reagent of the formulaR⁶ Li or an appropriate Grignard reagent of the formula R⁶ MgX wherein Xis chloro, bromo or iodo, and then oxidizing the reaction product. Theinitial reaction with the Grignard or organolithium reagent is generallyconducted in a hydrocarbon solvent such as n-pentane, n-hexane orn-heptane, at a temperature from about -70° C. to about 0° C.,preferably from about -70° C. to about -20° C. The subsequent oxidationstep may be carried out as described above for the oxidation ofcompounds wherein R¹ is hydroxymethyl.

Compounds of the formula IA wherein R¹ is ##STR42## and Y is hydrogenmay be prepared by reacting the corresponding compounds wherein R¹ is##STR43## with an organolithium reagent of the formula R⁷ Li or anappropriate Grignard reagent of the formula R⁷ MgX, in the mannerdescribed above for preparing compounds of the formula I wherein R¹ is##STR44## and R⁶ is other than hydrogen. Treatment of the resultingcompounds with an appropriate reagent of the formula Y--L, wherein Y isother than hydrogen and L is a leaving group, in the presence of astrong base yields the corresponding compounds wherein R¹ is ##STR45##and Y is other than hydrogen. Examples of bases that may be used aresodium hydride in dimethylformamide and a (C₁ -C₆)alkylithium in ahydrocarbon solvent (e.g. n-pentane or n-hexane). Suitable leavinggroups include chloro, bromo, iodo and OSO₂ --(C₁ -C₆)-alkyl. Thereaction temperature can range from about -20° C. to about 100° C., andis preferably from about 0° C. to about 60° C.

Scheme 2 illustrates the preparation of compounds of the formula IAwherein R¹ is a group of the formula ##STR46## Referring to scheme 2,such compounds may be prepared by reacting the corresponding compoundswherein R¹ is ##STR47## with a Wittig reagent of the formula ##STR48##Typically, this reaction is carried out in a nonprotic solvent such asdimethylformamide or a (C₄ -C₆)alkylether, preferably tetrahydrofuran,at a temperature from about 0° C. to about 100° C., preferably fromabout 25° C. to about 100° C. The reactants in which R¹ is ##STR49## maybe obtained by oxidation of the corresponding compounds wherein R¹ is--CHOHW as described above for the oxidation of compounds wherein R¹ is--CHOHR⁶. Similarly, those compounds wherein R¹ is --CHOHW may beobtained by the procedure described above and depicted in scheme 1 forpreparing the analogous compounds wherein R¹ is --CHOHR⁶ or --CHOHR⁷.

Compounds of the formula IA wherein R¹ is a group of the formula##STR50## may be formed by hydrogenation of the corresponding compoundswherein R¹ is ##STR51## in the presence of a metal containing catalyst.Suitable hydrogenation catalysts include palladium, platinum, nickel,platinum oxide and rhodium. The preferred catalyst for hydrogenation isplatinum on carbon. The reaction temperature may range from about 10° C.to about 50° C., with about 25° C. being preferred. The hydrogenation isgenerally carried out at a pressure from about 1.5 to about 4atmospheres, preferably at about 3.0 atmospheres, in a suitable inertsolvent such as acetic acid or a lower alcohol, preferably methanol,with about a stoichiometric quantity of hydrogen chloride present.

Compounds of the formula IA wherein R¹ is optionally substituted aryl,optionally substituted heteroaryl, dihydroxy-(C₁ -C₆)alkyl or (C₁-C₆)alkyl--S--(C₁ -C₆)alkyl may be prepared according to the reactionsequence illustrated and scheme 3. This reaction sequence is the same asthat described in European Patent Applications 470616A2 and 384370A1,referred to above, with the exception that a compound of the formula R¹C═NHNH₂, wherein R¹ is defined as above, is used as a starting material.The conditions, reagents and catalysts, etc. used in the reactions ofscheme 3 are set forth in detail in the foregoing patent applications,which, as indicated above, have been incorporated herein by reference intheir entirety.

Referring to scheme 3, a compound of formula II or its acid additionsalt is reacted with a compound of formula III to give a compound offormula IV. The reaction is generally conducted or an alcoholic solventsuch as methanol, ethanol or tert-butanol, at a temperature from about25° C. to about 100° C., preferably from about 25° C. to about 50° C.When an acid addition salt of a compound of formula II is employed, thereaction is generally conducted as above in the presence of an alkalimetal or alkaline earth metal hydroxide (e.g., sodium, potassium, orcalcium hydroxide) or an alkali metal alkoxide (e.g., sodium orpotassium ethoxide or tert-butoxide) at temperatures ranging from about10° C. to about 80° C., preferably at temperatures between 30° and 60°C.

The compound of formula IV is converted into a pyrimidine derivative ofthe formula V by reacting it with an inorganic acid chloride, e.g.,phosphorus oxychloride, thienyl chloride, phosphorus pentachloride orphosphorous trichloride. This reaction is usually conducted in anaromatic hydrocarbon solvent, e.g., benzene, toluene or xylene, at atemperature from about 30° to about 100° C. The preferred temperaturerange is between 30° and 60° C.

Reaction of the compound of formula V with the appropriate compound offormula NHR² R³ yields a compound of formula IA. Suitable solvents forthis reaction include ethereal solvents such as ethyl ether,tetrahydrofuran, or dioxane and halocarbon solvents such as methylenechloride or chloroform. The reaction temperature may range from about 0°C. to about 80° C. Preferably, the solvent is a halocarbon solvent andthe temperature is between 0° C. and 50° C.

Compounds of the formula IA wherein R¹ is (C₁ -C₆)alkoxycarbonyl-(C₁-C₆)alkyl may be prepared by reacting the corresponding compoundswherein R¹ is hydroxy-(C₁ -C₆)alkyl with the appropriate (C₁-C₅)alkanoic acid chloride in the presence of an organic base. Examplesof suitable organic bases are (C₄ -C₁₀)alkylamines and dialkylamines,pyridine, quinoline and isoquinoline. Generally, this reaction iscarried out in another or halocarbon solvent such as diethyl ether,tetrahydrofuran (THF), methylene chloride or chloroform, at atemperature from about 0° C. to about 50° C., preferably from about 0°C. to about room temperature.

Compounds of the formula IA wherein R¹ is (C₁ -C₆)alkoxycarbonylaryl canbe prepared in a similar manner, using the appropriate aroyl chloride inplace of a (C₁ -C₅)alkanoic acid chloride.

Compounds of the formula IA wherein R¹ is (C₁ -C₆)alkyl--SO--(C₁-C₆)alkyl may be prepared by oxidation of the corresponding compoundswherein R¹ is (C₁ -C₆)alkyl--S--(C₁ -C₆)alkyl using methods well knownto those skilled in the art. For example, these oxidations may beconducted using m-chloroperbenzoic acid as the oxidizing agent in ahalocarbon solvent such as methylene chloride or chloroform, at atemperature from about -10° C. to about 10° C., preferably about 0° C.Similarly, compounds of the formula IA wherein R¹ is (C₁ -C₆)alkyl--SO₂--(C₁ -C₆)alkyl may be prepared by oxidation of the correspondingcompounds wherein R¹ is (C₁ -C₆)alkyl--SO--(C₁ -C₆)alkyl using methodsknown in the art. Such oxidations may be conducted, for example, in themanner specified above, but at a temperature ranging from about roomtemperature to about 60° C., preferably at about the reflux temperatureof the solvent.

Compounds of the formula VI can be prepared using methods that are wellknown in peptide chemistry. Some of these procedures are describedbelow.

Compounds of the formula VI wherein R²⁵ is ##STR52## and Y² is absentcan be prepared as follows. A compound of the formula ##STR53## is firstconverted into its corresponding acid chloride, ##STR54## by reacting itwith thionyl chloride in a suitable aromatic or halocarbon solvent(e.g., benzene, toluene, xylene, methylene chloride or chloroform), at atemperature from about 0° C. to about 130° C., preferably from about 20°C. to about 100° C. The acid chloride is then reacted with a compoundhaving the following formula ##STR55## to produce the correspondingcompound of formula VI wherein Y² is absent. This reaction is generallycarried out in a halocarbon, aromatic hydrocarbon or ethereal solvent ata temperature from about 0° C. to about 150° C., preferably from about0° C. and about 100° C. Preferred solvents include benzene, toluene,xylene, methylene chloride, chloroform, ether, tetrahydrofuran anddioxane.

Alternatively, compounds of the formula VI wherein Y² is absent can beprepared by reacting a compound of the formula ##STR56## with a (C₄-C₈)alkylchloroformate in the presence of any organic base, and thenadding a compound of the formula XX, as depicted and defined above, tothe reaction mixture. Examples of bases that may be used are (C₃-C₆)alkylamines and aromatic amines such as pyridine, quinoline orisoquinoline. This reaction is typically conducted in a halocarbonsolvent, preferably methylene chloride or chloroform, at a temperaturefrom about -70° C. to about 50° C., preferably from about -70° C. toabout 20° C.

The addition of the compound of formula XX is typically carried out attemperatures ranging from about -70° C. to about 50° C., preferably fromabout -70° C. and about 30° C.

Compounds for the formula VI wherein R²⁵ is ##STR57## and Y² is##STR58## can be prepared by the following procedure. A compound of theformula XX, as depicted and defined above, is reacted with phosgene, toobtain a compound of the formula ##STR59## This reaction is conducted inthe presence of a base (e.g., a (C₃ -C₁₀)alkylamine or an aromatic aminesuch as pyridine, quinoline or isoquinoline) at a temperature from about-70° C. to about 0° C., preferably from about -30° C. to about 0° C.Appropriate solvents include ethereal, halocarbon and (C₅ -C₁₀)hydrocarbon solvents. Ether, dioxane, tetrahydrofuran, pentane, hexane,methylene chloride and chloroform are preferred. The compound of formulaXXI formed in the above reaction is then reacted with a compound of theformula ##STR60## in the presence of a base (e.g., a (C₃ -C₁₀)alkylamineor an aromatic amine such as pyridine, quinoline or isoquinoline). Thereaction is generally conducted at a temperature ranging from about -20°C. to about room temperature, preferably between about -10° C. and aboutroom temperature, in a halocarbon or ether solvent, preferably inmethylene chloride or chloroform.

Compounds of the formula VI wherein R²⁵ is ##STR61## and Y² is ##STR62##may be prepared in the following manner. First, a compound of theformula ##STR63## is contacted with an Ameberlite® IRA-904 resincontaining quaternary ammonium groups in the hydroxide form to yield asalt of the formula ##STR64## (hereinafter referred to as a salt of theformula XXII). Usually, the compound of formula ##STR65## is dissolvedin a lower alcohol or hydrocarbon solvent such as ethanol, diethyl etheror hexane and the reaction is carried out at a temperature from about10° C. to about 50° C., preferably at about room temperature. Then, acompound having a formula identical to formula VI except that R²⁵ isreplaced by a hydroxy group is reacted with a compound of the formula##STR66## wherein Y⁴ is hydrogen or (C₁ -C₅)alkyl, in the presence of anorganic base. Bases that may be used include (C₄ -C₁₀)alkylamines anddialkylamines, pyridine, quinoline and isoquinoline. Suitable solventsinclude ether and hydrocarbon solvents such as diethyl ether, methylenechloride, tetrahydrofuran and chloroform. Reaction temperatures mayrange from about 0° C. to about 50° C., and are preferably between about0° C. and about room temperature.

The foregoing reaction produces a compound of the formula VI wherein R²⁵is ##STR67## which is then reacted with the salt of formula XXII toproduce the desired compound of formula VI. This reaction is generallyconducted in an ether, halocarbon or hydrocarbon solvent (e.g., diethylether, hexane, methylene chloride or chloroform) at a temperature fromabout room temperature to about 60° C., preferably at about roomtemperature.

Compounds of the formula VI wherein R²⁵ is ##STR68## may be prepared byreacting a compound of the formula ##STR69## with a compound of theformula O₂ NCH₂ SO₂ --R²⁶ --NH₂.

Typically, this reaction is carried out in an ethereal, halocarbon orhydrocarbon solvent at temperatures from about -70° C. to about 0° C.Preferably, it is carried out in ether, tetrahydrofuran, dioxane,hexane, pentane, methylene chloride or chloroform at a temperature fromabout -30° C. to about 0° C.

Alternatively, such compounds can be prepared by reacting an isocyanateof the formula ##STR70## with a compound of the formula XX, as depictedand defined above. Suitable and preferred solvents for this reaction aresimilar to those specified for the preceding reaction. This reaction isusually conducted at a temperature ranging from about ambienttemperature to about 150° C., preferably from about ambient temperatureto about 100° C.

The starting material of the formula XXIII can be prepared from thecompound ##STR71## using standard methods described in the scientificliterature.

In each of the reactions discussed or illustrated above, pressure is notcritical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5.0 atmospheres are generally acceptable, andambient pressure, i.e., about one atmosphere, is preferred as a matterof convenience. Reaction times also are not critical unless otherwiseindicated. Reaction times from about 0.5 hours to about 3 hours aregenerally acceptable, though longer reaction times (e.g., 24 or 48hours) may be employed as a matter of convenience. Reaction times aremonitored by thin layer chromatography.

The pharmaceutically acceptable acid addition salts of the compounds ofthe formulae I and VI that are basic in nature may be prepared in aconventional manner by treating a solution or suspension of the freebase of formula I or VI with about one chemical equivalent of apharmaceutically acceptable acid. Conventional concentration andrecrystallization techniques are employed in isolating the salts.

The pharmaceutically acceptable base addition salts of compounds of theformulae I and VI that are acidic in nature may be formed withpharmaceutically acceptable cations by conventional methods. Thus, thesesalts may be readily prepared by treating the compound of formula I orVI with an aqueous solution of the desired pharmaceutically acceptablecation and evaporating the resulting solution to dryness, preferablyunder reduced pressure. Alternatively, a lower alkyl alcohol solution ofthe compound of formula I or VI may be mixed with an alkoxide of thedesired metal and the solution subsequently evaporated to dryness.

Compounds of the formula I, the pharmaceutically acceptable salts ofsuch compounds, mutual prodrugs of such compounds and aldose reductaseinhibitors (including the mutual prodrugs of the formula VI), thepharmaceutically acceptable salts of such mutual prodrugs, andcompositions comprising a compound of the formula I or apharmaceutically acceptable salt thereof and an aldose reductaseinhibitor or a pharmaceutically acceptable salt thereof (includingcompositions containing a compound of the formula I and a compound ofthe formula XV, XVI, XVII, XVIII or XIX) are hereinafter referred to,collectively, as "the active compounds and compositions of thisinvention".

The active compounds and compositions of this invention may beadministered to a subject in need of treatment by a variety ofconventional routes of administration, including orally, parenterallyand topically. In general, compounds of the formula I and theirpharmaceutically acceptable salts will be administered orally orparenterally at dosages between about 0.1 and about 50 mg/kg body weightof the subject to be treated per day, preferably from about 0.1 to 15mg/kg, in single or divided doses. Mutual prodrugs of compounds of theformula I and aldose reductase inhibitors will generally be administeredorally or parenterally at dosages between about 5 and about 100 mg/kgbody weight of the subject to be treated per day, preferably from about5 to about 25 mg/kg, in single or divided doses. Compositions containingboth a compound of the formula I and an aldose reductase inhibitor willgenerally be administered orally or parenterally at dosages betweenabout 1 and about 100 mg of each active component (i.e., the compound offormula I and the aldose reductase inhibitor) per kg body weight of thesubject to be treated per day, preferably from about 1 to about 25mg/kg. However, some variation in dosage will necessarily occurdepending on the condition of the subject being treated. The personresponsible for administration will, in any event, determine theappropriate dose for the individual subject.

The active compounds and compositions of this invention may beadministered alone or in combination with pharmaceutically acceptablecarriers, in either single or multiple doses. Suitable pharmaceuticalcarriers include inert solid diluents or fillers, sterile aqueoussolutions and various organic solvents. The pharmaceutical compositionsformed by combining the active compounds of this invention and thepharmaceutically acceptable carriers are then readily administered in avariety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such as sodiumcitrate, calcium carbonate and calcium phosphate may be employed alongwith various disintegrants such as starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Preferred materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof.

For parenteral administration, solutions of the active compounds andcompositions of this invention in sesame or peanut oil, aqueouspropylene glycol, or in sterile aqueous solutions may be employed. Suchaqueous solutions should be suitably buffered if necessary and theliquid diluent first rendered isotonic with sufficient saline orglucose. These particular aqueous solutions are especially suitable forintravenous, intramuscular, subcutaneous and intraperitonealadministration. In this connection, the sterile aqueous media employedare all readily available by standard techniques known to those skilledin the art.

The active compounds and compositions of this invention may be moreparticularly employed in the preparation of ophthalmic solutions. Suchophthalmic solutions are of principal interest for the treatment ofdiabetic cataracts by topical administration. For the treatment ofdiabetic cataracts, the active compounds and compositions of thisinvention are administered to the eye in the form of an ophthalmicpreparation prepared in accordance with conventional pharmaceuticalpractice. The ophthalmic preparation will contain a compound of theformula I, a mutual prodrug of a compound of the formula I and an aldosereductase inhibitor, or a pharmaceutically acceptable salt of suchcompound of formula I or prodrug, in a concentration from about 0.01 toabout 1% by weight, preferably from about 0.05 to about 0.5%, in apharmaceutically acceptable solution, suspension or ointment. Inopthalmic preparations containing a combination of a compound of theformula I and an aldose reductase inhibitor, each active ingredient willbe present in an amount from about 0.005 to about 1% by weight,preferably from about 0.005 to about 0.25%, in a pharmaceuticallyacceptable solution, suspension or ointment.

EXAMPLES General Experimental Procedure

Male Sprague-Dawley rats (350-400 g) were used for these experiments.Diabetes was induced in some of the rats by a tail vein injection ofstreptozocin, 85 mg/kg. Twenty-four hours later, 4 groups of diabeticrats were given a single dose of 4-4-(N,N-dimethylsulfamoyl)-piperazino!-2-methylpyrimidine (10, 50, 100,or 300 mg/kg) by oral gavage. Animals were sacrificed 4-6 hours afterdosing and blood and sciatic nerves were harvested. Tissues and cellswere extracted with 6% perchloric acid.

Sorbitol in erythrocytes and nerves was measured by a modification ofthe method of R. S. Clements et al. (Science, 166: 1007-8, 1969).Aliquots of tissue extracts were added to an assay system which hadfinal concentrations of reagents of 0.033M glycine, pH 9.4, 800 μMβ-nicotine adenine dinucleotide, and 4 units/ml of sorbitoldehydrogenase. After incubation for 30 minutes at room temperature,sample fluorescence was determined on a fluorescence spectrophotometerwith excitation at 366 nm and emission at 452 nm. After subtractingappropriate blanks, the amount of sorbitol in each sample was determinedfrom a linear regression of sorbitol standards processed in the samemanner as the tissue extracts.

Fructose was determined by a modification of the method described by M.Ameyama, Methods in Enzymology, 89: 20-25 (1982). Resazurin wassubstituted for ferricyanide. Aliquots of tissue extracts were added tothe assay system, which had final concentrations of reagents of 1.2Mcitric acid, pH 4.5, 13 μM resazurin, 3.3 units/ml of fructosedehydrogenase and 0.068% Triton X-100. After incubation for 60 minnutesat room temperature, sample fluorescence was determined on afluorescence spectrophotometer with excitation at 560 nm and emission at580 nm. After subtracting appropriate blanks, the amount of fructose ineach sample was determined from a linear regression of fructosestandards processed in the same manner as the tissue extracts.

SDH activity was measured by a modification of the method described byU. Gerlach, Methodology of Enzymatic Analyses, edited by H. U.Bergmeyer, 3, 112-117 (1983). Aliquots of sera or urine were added tothe assay system, which had final concentrations of reagents of 0.1Mpotassium phosphate buffer, pH 7.4, 5 mM NAD, 20 mM sorbitol, and 0.7units/ml of sorbitol dehydrogenase. After incubation for 10 minutes atroom temperature, the average change in sample absorbance was determinedat 340 nm. SDH activity was presented as milliOD₃₄₀ units/minute (OD₃₄₀=optical density at 340 nm).

Results

As shown in FIG. 1, 4-4-(N,N-dimethylsulfamoyl)-piperazino!-2-methylpyrimidine ("Compound 1")dose dependently lowered erythrocyte (red blood cell--"RBC") fructose indiabetic rats. It dose dependently raised erythrocyte sorbitol indiabetic rats (FIG. 2). A similar lowering of fructose with an increasein sorbitol was seen in the sciatic nerve of diabetic rats (FIGS. 3 and4).

This pattern of lowered fructose coupled with elevated sorbitol isconsistent with that expected of an inhibitor of sorbitol dehydrogenase(SDH), the enzyme that converts sorbitol to fructose. However, whentested directly on sorbitol dehydrogenase in vitro, 4-4-(N,N-dimethylsulfamoyl)-piperazino!-2-methylpyrimidine exhibited anIC₅₀ value of 0.5 mM. On the other hand, we discovered that sera fromrats dosed with 4-4-(N,N-dimethylsulfamoyl)-piperazino!-2-methylpyrimidine potentlyinhibited SDH in vitro in a dose dependent manner (FIG. 5).

The urine of animals dosed with 4-4-(N,N-dimethylsulfamoyl)-piperazino!-2-methylpyrimidine also potentlyinhibited SDH in vitro in a dose dependent manner (FIG. 6). Comparisonwith results for the sera (FIG. 5) shows that the urine was an even morepotent source of SDH inhibitory activity, with strong inhibition of SDHfound with as little as 0.5 μl of urine.

Examples 1, 2 and 3

Example 1: 4- 4-(N-methylsulfamoyl)-piperazino!-2-methylpyrimidine

Example 2: 4-4-N-methylsulfamoyl)-piperazino!-2-hydroxy-methylpyrimidine

Example 3: 4 4-N-sulfamoyl)-piperazino!-2-methylpyrimidine

An aqueous suspension of 4-4-(N,N-dimethylsulfamoyl)-piperazino!-2-methylpyrimidine ("Compound 1"),prepared as described in European Patent Application 384,370A1, wasadministered by oral garage to male CD rats (350-430 g body weight) at adose of 100 mg/kg. The rats were housed in appropriate cages and theirurine (220 mL) was collected overnight. The urine was extracted withethyl acetate (75 mL) and the resulting emulsion was filtered through asupercel pad and the filtrate was collected. The ethyl acetate layer wasseparated and the aqueous layer was extracted again (3×75 mL). The ethylacetate extracts were combined and dried over anhydrous magnesiumsulfate to obtain a crude oily residue (0.8 g). This residue wasdissolved in 10 mL of a 9:1 mixture of methylene chloride and ethanoland chromatographed using a Chromatotron. The Chromatotron plate waseluted with a mixture of 19:1 of methylene chloride and ethanol andfractions were collected in 5 mL portions. Evaporation of the first 20×5mL portions gave the title compound of Example 1 (6.9 mg): ¹ H NMR(DMSO, 500 MHz) δ 2.37 (s, 3H), 2.55 (d, J=7 Hz, 3H), 3.13 (m, 4H), 3.7(m, 4H), 6.68 (d, J=8 Hz, 1H), 7.72 (m, 1H), 8.13 (d, J=8 Hz, 1H). Thenext 20×5 mL portions yielded the title compound of Example 2 (24 mg): ¹H NMR (DMSO, 500 MHz) δ 2.48 (d, J=7 Hz, 3H), 3.1 (m, 4H), 3.58 (m, 4H),4.36 (s, 2H), 6.1 (s, 1H), 6.33 (d, J=8 Hz, 1H), 6.5 (m, 1H), 8.03 (d,J=8 Hz, 1H). The last 20×5 mL portions gave the title compounds ofExample 3 (15 mg): ¹ H NMR (DMSO, 500 MHz) δ 2.34 (s, 3H), 3.04 (m, 4H),3.65 (m, 4H), 6.35 (d, J=8 Hz, 1H), 7.93 (d, J=8 Hz, 1H).

Example 4

4 4-(N,N-Dimethylsulfamoyl)piperizino!-2-hydroxymethylpyrimidine

The title compound was prepared as described in European PatentApplication 70,616A2, published Feb. 12, 1992.

The structures and IC₅₀ values of 4-4-(N,N-dimethylsulfamoyl)-piperazino!-2-methylpyrimidine and the titlecompounds of Example 1-4 are set forth in Table I below. The IC₅₀ valuesindicate the concentration at which fifty percent inhibition of sorbitoldehydrogenase in vitro was observed.

                                      TABLE 1                                     __________________________________________________________________________     ##STR72##                                                                    __________________________________________________________________________

Example 5

44-(N,N-Dimethylsulfamoyl)piperizinol!pyrimidine-2-ylmethyl-3,4-dihydro-4-oxo-3-(5-trifluoromethyl)-2-benzothiazolyl!-methyl!-1-phthalazine acetate

A solution of 3,4-dihydro-4-oxo-3-(5-trifluoromethyl)-2-benzothiazolyl!-methyl!-1-phthalazineacetic acid(839 mg, 2 mmol) in methylene chloride (10 mL) containing triethylamine(0.28 mL, 2 mmol) was added to a solution of isobutyl chloroformate (0.2mL, 2 mmol) in methylene chloride (10 mL) at a temperature between -78°and -65° C. After 30 minutes, a solution of 44-(N,N-dimethylsulfamoyl)piperizino!-2-hydroxymethylpyrimidine inmethylene chloride (5 mL) was added to the reaction mixture. Thereaction was allowed to warm to room temperature, stirred for 2 hoursand then quenched with water (20 mL). The methylene chloride layer wascollected and was washed succesively with 5% sodium bicarbonate solutionand water. The organic layer was dried, evaporated and the residue waschromatographed over silica gel. Elution with a solution of methylenechloride in methanol (95:5) and evaporation of the eluent gave the titlecompound (0.35 g). M.P. 97°-99° C.

We claim:
 1. A compound of the formula ##STR73## wherein R¹ is (C₁-C₆)alkoxycarbonyl-(C₁ -C₆)alkyl, (C₁ -C₆)alkyl--S--(C₁ -C₆)alkyl, (C₁-C₆)alkyl--SO--(C₁ -C₆)alkyl, (C₁ -C₆)alkyl--SO₂ --(C₁ -C₆)alkyl,heteroaryl, heteroaryl-(C₁ -C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonylaryl, aryl-(C₁ -C₆)alkyloxy or heteroaryl-(C₁-C₆)alkyloxy, wherein said aryl and the aryl moieties of said aryl-(C₁-C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl, and aryl-(C₁ -C₆)alkyloxy areindependently selected from phenyl and naphthyl, and wherein saidheteroaryl and the heteroaryl moieties of said heteroaryl-(C₁ -C₆)alkyland heteroaryl-(C₁ -C₆)alkyloxy are independently selected from pyridyl,furyl, tetrahydrofuryl, thienyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, oxazolyl and benzothiazolyl, and wherein said aryl andheteroaryl and the aryl and heteroaryl moieties of said heteroaryl-(C₁-C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl, aryl-(C₁-C₆)alkyloxy and heteroaryl-(C₁ -C₆)alkyloxy may optionally besubstituted with one or more substituents independently selected fromchloro, bromo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl,--SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl, hydroxy-(C₁ -C₆)alkyl andtrifluoromethyl;or R¹ is a group of the formula ##STR74## wherein thedotted line represents an optional double bond, W, Q and Z areindependently selected from hydrogen, (C₁ -C₆)alkyl and trifluoromethyl,phenyl, furyl, triazolyl, thiazolyl and thienyl, wherein said phenyl,furyl, triazolyl, thiazolyl and thienyl may optionally be substitutedwith one or more substituents, preferably with from zero to twosubstituents, independently selected from (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy,trifluoromethyl and hydroxy, with the proviso that only one of W, Z or Qcan be hydrogen or alkyl; or R¹ is a group of the formula --(C═O)R⁶,wherein R⁶ is hydrogen, (C₁ -C₆)alkyl, aryl selected from phenyl andnaphthyl, or heteroaryl selected from pyridyl, furyl, thienyl,imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl,benzofuranyl and benzothienyl, wherein said aryl and heteroaryl groupsmay optionally be substituted with one or more substituents, preferablywith from zero to two substituents, independently selected from chloro,bromo, nitro, trifluoromethyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl,--SO--(C₁ -C₆)alkyl and --SO₂ --(C₁ -C₆)alkyl; or R¹ is a group of theformula ##STR75## wherein R⁷ is aryl selected from phenyl and naphthyl,or heteroaryl selected from pyridyl, furyl, thienyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl,benzothienyl and quinolyl, wherein said aryl and heteroaryl groups mayoptionally be substituted with one or more substituents, preferably withfrom zero to two substituents, independently selected from chloro,bromo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁-C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and trifluoromethyl, and Y is hydrogen,benzyl, acetyl, benzoyl, aryl selected from phenyl and naphthyl,heteroaryl selected from furyl, thienyl, thiazolyl and oxazolyl, whereinsaid aryl and heteroaryl groups may optionally be substituted with oneor more substituents, preferably with from zero to two substituents,independently selected from chloro, bromo, nitro, trifluoromethyl, (C₁-C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl and--SO₂ --(C₁ -C₆)alkyl; R² and R³ are independently selected fromhydrogen, (C₁ -C₆)alkyl, phenyl and phenyl-(C₁ -C₄)alkyl, wherein saidphenyl and the phenyl moiety of said phenyl-(C₁ -C₄)alkyl may optionallybe substituted with one or more substituents independently selected from(C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, chloro, bromo and trifluoromethyl; or R²and R³ form, together with the nitrogen to which they are attached, acyclic group selected from azetidino, pyrrolidino, piperidino,piperazino and morpholino, wherein said cyclic group may optionally besubstituted with from zero to two substituents, independently selectedfrom (C₁ -C₆)alkyl, --CONH₂, --SO₂ NH₂, N-(C₁ -C₄)alkylsulfamoyl,N,N-di-(C₁ -C₄)alkylsulfamoyl, (C₁ -C₆)alkoxycarbonyl, N,N-di-(C₁-C₄)alkylcarbamoyl, N-(C₁ -C₄)-alkylcarbamoyl, N-phenylcarbamoyl, (C₁-C₆)alkylcarbonyl, phenylcarbonyl, (C₁ -C₆)alkylsulfonyl, (C₁-C₆)alkylsulfinyl, phenylsulfonyl, heteroarylsulfonyl andheteroarylcarbonyl, wherein the heteroaryl moieties of saidheteroarylcarbonyl and heteroarylsulfonyl are selected from furyl,thienyl, thiazolyl, and oxazolyl, and wherein the phenyl moieties ofsaid phenylcarbonyl, N-phenylcarbamoyl, phenylcarbonyl andphenylsulfonyl may optionally be substituted with one or moresubstituents, independently selected from (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy,chloro, bromo, nitro, amino, cyano and trifluoromethyl; R⁴ is hydrogen,chloro, bromo, cyano, nitro, trifluoromethyl, amino, (C₁ -C₆)alkyl, (C₁-C₆)hydroxyalkyl, (C₁ -C₆)alkoxy, phenyl, naphthyl or furyl, whereinsaid phenyl, naphthyl and furyl may optionally be substituted with oneor more substituents, independently selected from chloro, bromo,trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl,--SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy; and R⁵ ishydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, trifluoromethyl, (C₁-C₆)hydroxyalkyl, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, phenyl or furyl, wherein said phenyl and furyl may optionallybe substituted with one or more substituents, independently selectedfrom chloro, bromo, trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy,--SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy; or apharmaceutically acceptable salt of such compound.
 2. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and anamount of a compound of the formula ##STR76## wherein R¹ is hydrogen,CF₃, (C₁ -C₆)alkyl, (C₁ -C₆)alkyl--S--(C₁ -C₆)alkyl, (C₁-C₆)alkyl--SO--(C₁ -C₆)alkyl, (C₁ -C₆)alkyl--SO₂ --(C₁ -C₆)alkyl,hydroxy-(C₁ -C₆)alkyl, dihydroxy-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, (C₁-C₆)alkoxycarbonyl-(C₁ -C₆)alkyl, aryl selected from phenyl andnaphthyl, aryl-(C₁ -C₆)alkyl wherein the aryl moiety is selected fromphenyl and naphthyl, (C₁ -C₆)alkoxycarbonylaryl wherein the aryl moietyis selected from phenyl and naphthyl, aryl-(C₁ -C₆)alkyl wherein thearyl moiety is selected from phenyl and naphthyl, aryl-(C₁ -C₆)alkyloxywherein the aryl moiety is selected from phenyl and napthyl, heteroarylselected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl,and benzothienyl; heteroaryl-(C₁ -C₆)alkyl wherein heteroaryl is definedas above, or heteroaryl-(C₁ -C₆)alkyloxy wherein heteroaryl is definedas above, and wherein said aryl and heteroaryl groups, the aryl moietiesof said aryl-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl and aryl-(C₁-C₆)alkyloxy and the heteroaryl moiety of said heteroaryl-(C₁ -C₆)alkylmay optionally be substituted with one or more substituentsindependently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, hydroxy-(C₁ -C₆)alkyl and trifluoromethyl;or R¹ is a group ofthe formula ##STR77## wherein the dotted line represents an optionaldouble bond, W, Q and Z are independently selected from hydrogen, (C₁-C₆)alkyl and trifluoromethyl, phenyl, furyl, triazolyl, thiazolyl andthienyl, wherein said phenyl, furyl, triazolyl, thiazolyl and thienylmay optionally be substituted with one or more substituentsindependently selected from (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy,trifluoromethyl and hydroxy; or R¹ is a group of the formula ##STR78##wherein R⁶ is hydrogen, (C₁ -C₆)alkyl, aryl selected from phenyl andnaphthyl, or heteroaryl selected from pyridyl, furyl, thienyl,imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, benzothiazolyl,benzofuranyl and benzothienyl, wherein said aryl and heteroaryl groupsmay optionally be substituted with one or more substituentsindependently selected from chloro, bromo, nitro, trifluoromethyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl and --SO₂ --(C₁-C₆)alkyl; or R¹ is a group of the formula ##STR79## wherein R⁷ is arylselected from phenyl and naphthyl, or heteroaryl selected from pyridyl,furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl,benzothiazolyl, benzofuranyl, benzothienyl and quinolyl, wherein saidaryl and heteroaryl groups may optionally be substituted with one ormore substituents, preferably with from zero to two substituents,independently selected from chloro. bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl and trifluoromethyl, and Y is hydrogen, benzyl, acetyl,benzoyl, aryl selected from phenyl and naphthyl, heteroaryl selectedfrom furyl, thienyl, thiazolyl and oxazolyl, wherein said aryl andheteroaryl groups may optionally be substituted with one or moresubstituents independently selected from chloro, bromo, nitro,trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl,--SO--(C₁ -C₆)alkyl and --SO₂ --(C₁ -C₁)alkyl; R² and R³ areindependently selected from hydrogen, (C₁ -C₆)alkyl, phenyl andphenyl-(C₁ -C₄)alkyl, wherein said phenyl and the phenyl moiety of saidphenyl-(C₁ -C₄)alkyl may optionally be substituted with one or moresubstituents independently selected from (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy,chloro, bromo and trifluoromethyl; or R² and R³ form, together with thenitrogen to which they are attached, a cyclic group selected fromazetidino, pyrrolidino, piperidino, piperazino and morpholino, whereinsaid cyclic group may optionally be substituted with from zero to twosubstituents, independently selected from (C₁ -C₆)alkyl, --CONH₂, --SO₂NH₂, N-(C₁ -C₄)alkylsulfamoyl, N,N-di-(C₁ -C₄)alkylsulfamoyl, (C₁-C₆)alkoxycarbonyl, N,N-di-(C₁ -C₄)alkylcarbamoyl, N-(C₁-C₄)alkylcarbamoyl, N-phenylcarbamoyl, (C₁ -C₆)alkylcarbonyl,phenylcarbonyl, (C₁ -C₆)alkylsulfonyl, (C₁ -C₆)alkylsulfinyl,phenylsulfonyl, heteroarylsulfonyl and heteroarylcarbonyl, wherein theheteroaryl moieties of said heteroarylcarbonyl and heteroarylsulfonylare selected from furyl, thienyl, thiazolyl, and oxazolyl, and whereinthe phenyl moieties of said phenylcarbonyl, N-phenylcarbamoyl,phenylcarbonyl and phenylsulfonyl may optionally be substituted with oneor more substituents independently selected from (C₁ -C,)alkyl, (C₁-C₄)alkoxy, chloro, bromo, nitro, amino, cyano and trifluoromethyl; R⁴is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino, (C₁-C₆)alkyl, (C₁ -C₆)hydroxyalkyl, (C₁ -C₆)alkoxy, phenyl, naphthyl orfuryl, wherein said phenyl, naphthyl and furyl may optionally besubstituted with one or more substituents independently selected fromchloro, bromo, trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁-C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy; andR⁵ is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, trifluoromethyl, (C₁-C₆)hydroxyalkyl, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, phenyl or furyl, wherein said phenyl and furyl may optionallybe substituted with one or more substituents independently selected fromchloro, bromo, trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --SO--(C₁-C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy; or a pharmaceuticallyacceptable salt thereof, effective in (a) inhibiting the enzyme sorbitoldehydrogenase, (b) lowering the level of fructose in one or more of thetissues of a mammal that are affected by diabetes, or (c) treating orpreventing a diabetic complication in a mammal.
 3. A pharmaceuticalcomposition according to claim 2, wherein the compound of formula I is acompound wherein R¹ is (C₁ -C₆)alkoxycarbonyl-(C₁ -C₆)alkyl, (C₁-C₆)alkyl--S--(C₁ -C₆)alkyl, (C₁ -C₆)alkyl--SO--(C₁ -C₆)alkyl, (C₁-C₆)alkyl--SO₂ --(C₁ -C₆)alkyl, dihydroxy-(C₁ -C₆)alkyl, aryl,heteroaryl, heteroaryl-(C₁ -C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonylaryl, aryl-(C₁ -C₆)alkyloxy or heteroaryl-(C₁-C₆)alkyloxy, wherein said aryl and the aryl moieties of said aryl-(C₁-C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl, and aryl-(C₁ -C₆)alkyloxy areindependently selected from phenyl and naphthyl, and wherein saidheteroaryl and the heteroaryl moieties of said heteroaryl-(C₁ -C₆)alkyland heteroaryl-(C₁ -C₆)alkyloxy are independently selected from whereinthe aryl moiety is selected from phenyl and naphthyl, heteroarylselected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyl, andwherein said aryl and heteroaryl and the aryl and heteroaryl moieties ofsaid heteroaryl-(C₁ -C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonylaryl, aryl-(C₁ -C₆)alkyloxy and heteroaryl-(C₁-C₆)alkyloxy may optionally be substituted with one or more substituentsindependently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, hydroxy-(C₁ -C₆)alkyl and trifluoromethyl.
 4. Apharmaceutical composition according to claim 2, comprising an amount ofsaid compound of the formula I that is effective in inhibiting theenzyme sorbitol dehydrogenase.
 5. A pharmaceutical composition accordingto claim 2, comprising an amount of said compound of the formula I thatis effective in lowering the level of fructose in one or more of thetissues of a mammal that are affected by diabetes.
 6. A pharmaceuticalcomposition according to claim 2, comprising an amount of said compoundof the formula I that is effective in treating or preventing a diabeticcomplication in a mammal.
 7. A pharmaceutical composition according toclaim 6, wherein said diabetic complication is diabetic neuropathy,diabetic retinopathy, diabetic nephropathy, diabetic microangiopathy ordiabetic macroangiopathy.
 8. A pharmaceutical composition according toclaim 2 in unit dosage form.
 9. A pharmaceutical composition accordingto claim 2, in the form of a tablet suitable for oral administration.10. A pharmaceutical composition according to claim 2, in the form of asolution suitable for parenteral administration.
 11. A pharmaceuticalcomposition according to claim 2, in the form of a solution suitable forophthalmic administration.
 12. A mutual prodrug of a compound accordingto claim 1 and an aldose reductase inhibiting compound.
 13. A mutualprodrug of a compound of the formula I, as defined in claim 2, or apharmaceutically acceptable salt thereof, and an aldose reductaseinhibiting compound.
 14. A compound of the formula ##STR80## wherein R²⁵is ##STR81## and R²⁶ is aryl selected from phenyl and naphthyl, whereinsaid aryl may optionally be substituted with one or more substituentsindependently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, hydroxy-(C₁ -C₆)alkyl and trifluoromethyl;R² and R³ areindependently selected from hydrogen, (C₁ -C₆)alkyl, phenyl andphenyl-(C₁ -C₄)alkyl, wherein said phenyl and the phenyl moiety of saidphenyl-(C₁ -C₄)alkyl may optionally be substituted with one or moresubstituents independently selected from (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy,chloro, bromo and trifluoromethyl; or R² and R³ form, together with thenitrogen to which they are attached, a cyclic group selected fromazetidino, pyrrolidino, piperidino, piperazino and morpholino, whereinsaid cyclic group may optionally be substituted with from zero to twosubstituents independently selected from (C₁ -C₆)alkyl, --CONH₂, --SO₂NH₂, N-(C₁ -C₄)alkylsulfamoyl, N,N-di-(C₁ -C₄)alkylsulfamoyl, (C₁-C₆)alkoxycarbonyl, N,N-di-(C₁ -C₄)alkylcarbamoyl, N-(C₁-C₄)-alkylcarbamoyl, N-phenylcarbamoyl, (C₁ -C₆)alkylcarbonyl,phenylcarbonyl, (C₁ -C₆)alkylsulfonyl, (C₁ -C₆)alkylsulfinyl,phenylsulfonyl, heteroarylsulfonyl and heteroarylcarbonyl, wherein theheteroaryl moieties of said heteroarylcarbonyl and heteroarylsulfonylare selected from furyl, thienyl, thiazolyl and oxazolyl, and whereinthe phenyl moieties of said phenylcarbonyl, N-phenylcarbamoyl,phenylcarbonyl and phenylsulfonyl may optionally be substituted with oneor more substituents independently selected from (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, chloro, bromo, nitro, amino, cyano and trifluoromethyl; R⁴is hydrogen, chloro, bromo, cyano, nitro, trifluoromethyl, amino, (C₁-C₆)alkyl, (C₁ -C₆)hydroxyalkyl, (C₁ -C₆)alkoxy, phenyl, naphthyl orfuryl, wherein said phenyl, naphthyl and furyl may optionally besubstituted with one or more substituents independently selected fromchloro, bromo, trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁-C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy; R⁵ ishydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, trifluoromethyl, (C₁-C₆)hydroxyalkyl, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, phenyl or furyl, wherein said phenyl and furyl may optionallybe substituted with one or more substituents independently selected fromchloro, bromo, trifluoromethyl, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --SO--(C₁-C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl and hydroxy; R⁸is hydrogen or R⁷ ; R⁷ is aryl selected from phenyl and naphthyl, orheteroaryl selected from pyridyl, furyl, thienyl, imidazolyl, pyrazolyl,triazolyl, thiazolyl, oxazolyl, benzothiazolyl, benzofuranyl,benzothienyl and quinolyl, wherein said aryl and heteroaryl groups mayoptionally be substituted with one or more substituents independentlyselected from chloro, bromo, (C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁-C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl andtrifluoromethyl, and Y is hydrogen, benzyl, acetyl, benzoyl, arylselected from phenyl and naphthyl, or heteroaryl selected from furyl,thienyl, thiazolyl and oxazolyl, wherein said aryl and heteroaryl groupsmay optionally be substituted with one or more substituentsindependently selected from chloro, bromo, nitro, trifluoromethyl, (C₁-C₆)alkyl, (C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl and--SO₂ --(C₁ -C₆)alkyl; ##STR82## or Y² is absent (i.e., the carbon towhich R⁸ is attached is directly bonded to ##STR83## Y⁴ is hydrogen or(C₁ -C₅)alkyl; and Y³ is selected from the following groups: ##STR84##wherein A is CH₂, CH₂ CH₂, CH(CH₃) or ##STR85## B is oxygen or sulfur;R⁹ is selected from phenyl, benzothiazol-2-yl, benzoxazol-2-yl,benzofuran-2-yl, benzothiophen-2-yl, thiazolopyridin-2-yl,oxazolopyridin-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, and5-phenyl-1,2,4-oxadiazol-3-yl, and R⁹ may optionally be substituted withfrom one to three substituents independently selected from fluorine,chlorine, bromine, methyl, methylthio, methoxy, hydroxy andtrifluoromethyl; R¹⁰ and R¹¹ are independently selected from hydrogen,fluorine, chlorine, bromine, (C₁ -C₄)alkyl, (C₁ -C₄)alkylthio, (C₁-C₄)alkoxy and trifluoromethyl; or R¹⁰ and R¹¹ together, with thecarbons to which they are attached, form a group of the formula##STR86## wherein p is 1 or 2; D and E are independently selected from--CH₂ --, oxygen and sulfur, except that D and E cannot both be oxygenand cannot both be sulfur; R¹² and R¹³ are independently selected fromhydrogen, fluorine, chlorine, bromine, (C₁ -C₄)alkyl, (C₁ -C₄)alkylthio,(C₁ -C₄)alkoxy and trifluoromethyl; and F and G are independentlyselected from --CH-- and nitrogen; R¹² and R¹³ are independentlyselected from hydrogen, fluorine, chlorine, bromine, (C₁ -C₄)alkyl, (C₁-C₄)alkylthio, (C₁ -C₄)alkoxy and trifluoromethyl; K is oxygen, sulfur,SO or SO₂ ; R¹⁴ is hydrogen, fluoro, chloro, bromo, methyl, nitro,cyano, methanesulfonyl or benzoyl; R¹⁵ is hydrogen, fluoro, chloro,bromo, carboxy, (C₁ -C₃)alkyl, (C₁ -C₃)alkoxy or benzyloxy; R¹⁶ ishydrogen, fluoro, chloro, bromo or (C₁ -C₃)alkyl; or R¹⁵ and R¹⁶,together with the carbon atoms to which they are attached, form a7,8-benzo ring; R¹⁷ is (C₁ -C₄)alkyl, trifluoromethyl or (CH₂)_(n) Ar,wherein n is 0, 1 or 2 and Ar is phenyl optionally substituted with oneor two substituents independently selected from methoxy, fluoro, chloroand bromo; R¹⁸ is hydrogen, methyl or ethyl; or R¹⁷ and R¹⁸, togetherwith the carbon to which they are attached, form a saturated 4 or 5membered carbocyclic spiro ring; and R¹⁹ is hydrogen or methyl; with theproviso that: (a) when K is other than oxygen, R¹⁴ is fluoro, chloro,cyano or nitro, and R¹⁵ and R¹⁶ do not form a 7,8-benzo ring; (b) when Kis other than oxygen or R¹⁷ is other than methyl, ethyl ortrifluoromethyl, both R¹⁸ and R¹⁹ are hydrogen; and (c) when Y³ is agroup of the formula XIVA, R⁹ is benzothiazol-2-yl or substitutedbenzothiazol-2-yl; or a pharmaceutically acceptable salt of suchcompound.
 15. A compound according to claim 14 wherein R²⁵ is ##STR87##Y² is not absent and: (a) Y³ is a group of the formula VII, R⁹ isphenyl, substituted phenyl, benzothiazol-2-yl or benzoxazol-2-yl, A is--CH₂ --, and R¹⁰ and R¹¹ are either both methyl or they form, togetherwith the carbons to which they are attached, a group of the formula##STR88## (b) Y³ is a group of the formula VIII, R⁹ is phenyl,Substituted phenyl, benzothiazol-2-yl or benzoxazol-2-yl, A is --OH₂ --,and R¹² and R¹³ are independently selected from bromo and chloro; (c) Y³is a group of the formula IX and each of R¹² and R¹³ is hydrogen; (d) Y³is a group of the formula X and R¹² and R¹³ are independently selectedfrom (C₁ -C₆)alkoxy and trifluoromethyl; (e) Y³ is a group of theformula XI and R¹² and R¹³ are independently selected from (C₁-C₆)alkyl; (f) Y³ is a group of the formula XII, R⁹ is phenyl,substituted phenyl or benzothiazol-2-yl, A is --CH₂ -- and R¹² and R¹³are independently selected from chloro and bromo; or (g) Y³ is a groupof the formula XIII, each of R¹⁴ and R¹⁹ is hydrogen, each of R¹⁷ andR¹⁸ is methyl, R¹⁵ is 6-chloro or 6-fluoro and R¹⁶ is 7-chloro or7-fluoro.
 16. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and an amount of a mutual prodrug of a compoundaccording to claim 1 and an aldose reductase inhibiting compound, or apharmaceutically acceptable salt of such a prodrug, that is effective in(a) inhibiting the enzyme sorbitol dehydrogenase, (b) lowering the levelof fructose in one or more of the tissues of a mammal that are affectedby diabetes, or (c) treating or preventing a diabetic complication in amammal.
 17. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and an amount of a mutual prodrug of an aldosereductase inhibiting compound and a compound of the formula I, asdefined in claim 2, or a pharmaceutically acceptable salt of such aprodrug, that is effective in (a) inhibiting the enzyme sorbitoldehydrogenase, (b) lowering the level of fructose in one or more of thetissues of a mammal that are affected by diabetes, or (c) treating orpreventing a diabetic complication in a mammal.
 18. A pharmaceuticalcomposition comprising: (a) an amount of a compound of the formula I, asdefined in claim 2, or a pharmaceutically acceptable salt thereof, thatis effective in lowering the level of fructose in one or more of thetissues of a mammal, that are affected by diabetics; (b) an amount of analdose reductase inhibiting compound, or a pharmaceutically acceptablesalt thereof, that is effective in lowering the level of fructose in oneor more of the tissues of a mammal that are affected by diabetes; and(c) a pharmaceutically acceptable carrier.
 19. A pharmaceuticalcomposition comprising (a) an amount of a compound of the formula I, asdefined in claim 2, or a pharmaceutically acceptable salt thereof,effective in treating or preventing a diabetic complication such asdiabetic neuropathy, diabetic retinopathy, diabetic nephropathy, ordiabetic microangiopathy or macroangiopathy in a mammal; (b) an amountof an aldose reductase inhibiting compound, or a pharmaceuticallyacceptable salt thereof, effective in treating or preventing a diabeticcomplication such as diabetic neuropathy, diabetic retinopathy, diabeticnephropathy or diabetic microangiopathy or macroangiopathy in a mammal;and (c) a pharmaceutically acceptable carrier.
 20. A pharmaceuticalcomposition comprising: (a) an amount of a compound of the formula I, asdefined in claim 2, or a pharmaceutically acceptable salt thereof, thatis effective in lowering the level of fructose in one or more of thetissues of a mammal that are affected by diabetics; (b) an amount of acompound of the formula XV wherein L is oxygen, CH₂ sulfur or ##STR89##J is hydrogen, methyl or ##STR90## G is CH or N; R²⁰ and R²¹ areindependently selected from hydrogen, fluorine, chlorine, (C₁ -C₆)alkyl,(C₁ -C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl or --SO₂ --(C₁-C₆)alkyl;M is phenyl, naphthyl or a heteroaryl group selected fromfuran, morpholine, pyrrolidine, tetrahydroisoquinoline, thiophene,thiazole, oxazole, benzofuran, benzothiophene, benzothiazole,benzoxazole and indole, wherein said phenyl, naphthyl and heteroarylgroups may optionally be substituted with up to three substituentsindependently selected from chloro, fluoro, bromo, cyano, nitro,hydroxy, carboxy, amino (C₁ -C₆)alkylamino, (C₁ -C₆)dialkylamino, (C₁-C₆)alkanoylamino, (C₁ -C₆)alkanoyl, (C₁ -C₆)alkyl, (C₂ -C₆)alkenyl, (C₃-C₆)alkenyloxy, fluoro-(C₁ -C₆)alkyl, (C₁ -C₆)alkoxy, fluoro-(C₁-C₄)alkoxy, (C₁ -C₆)hydroxyalkyl, carbamoyl, (C₁ -C₇)alkylcarbamoyl, (C₁-C₇)dialkylcarbamoyl, sulfamoyl, (C₁ -C₆)alkysulfamoyl, (C₁-C₆)dialkylsulfamoyl, (C₁ -C₆)alkoxycarbonyl, (C₁ -C₄)alkylenedioxy, (C₁-C₆)alkanesulfonamido, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂--(C₁ -C₆)alkyl, phenyl, phenoxy, benzyloxy, benzyloxycarbonyl,benzamido, and benzenesulfonamido, and wherein said phenyl and thephenyl moieties of said phenoxy, benzyloxy, benzyloxycarbonyl, benzamidoand benzenesulfonamido may optionally be substituted with a substituentselected from chlorine, fluorine, (C₁ -C₄)alkyl (C₁ -C₄)alkoxy and##STR91## wherein Y⁵ is oxygen or sulfur, or Y⁵ is absent (i.e., thephenyl ring is bonded to the carbon to which R²² and R²³ are attached),and R²² and R²³ are independently selected from hydrogen and (C₁-C₄)alkyl, and the phenyl moiety to which the --NHCOC(R²²)(R²³)--Y⁵ --sidechain is attached may optionally be substituted with from one tothree substituents independently selected from hydrogen, halo,trifluoromethyl, nitro, cyano, M is phenyl, naphthyl or a heteroarylgroup selected from furan, morpholine, pyrrolidine,tetrahydroisoquinoline, thiophene, thiazole, oxazole, benzofuran,benzothiophene, benzothiazole, benzoxazole and indole, wherein saidphenyl, naphthyl and heteroaryl groups may optionally be substitutedwith up to three substituents independently selected from chloro,fluoro, bromo, cyano, nitro, hydroxy, carboxy, amino (C₁ -C₆)alkylamino,(C₁ -C₆)dialkylamino, (C₁ -C₆)alkanoylamino, (C₁ -C₆)alkanoyl, (C₁-C₆)alkyl, (C₂ -C₆)alkenyl, (C₃ -C₆)alkenyloxy, fluoro-(C₁ -C₆)alkyl,(C₁ -C₆)alkoxy, fluoro-(C₁ -C₄)alkoxy, (C₁ -C₆)hydroxyalkyl, carbamoyl,(C₁ -C₇)alkylcarbamoyl, (C₁ -C₇)dialkylcarbamoyl, sulfamoyl, (C₁-C₆)alkysulfamoyl, (C₁ -C₆)dialkylsulfamoyl, (C₁ -C₆)alkoxycarbonyl, (C₁-C₄)alkylenedioxy, (C₁ -C₆)alkanesulfonamido, --S--(C₁ -C₆)alkyl,--SO--(C₁ -C₆)alkyl, --SO₂ --(C₁ -C₆)alkyl, phenyl, phenoxy, benzyloxy,benzyloxycarbonyl, benzamido, and benzenesulfonamido, and wherein saidphenyl and the phenyl moieties of said phenoxy, benzyloxy,benzyloxycarbonyl, benzamido and benzenesulfonamido may optionally besubstituted with a substituent selected from chlorine, fluorine, (C₁-C₄)alkyl (C₁ -C₄)alkoxy and ##STR92## wherein Y⁵ is oxygen or sulfur,or Y⁵ is absent (i.e., the phenyl ring is bonded to the carbon to whichR²² and R²³ are attached), and R²² and R²³ are independently selectedfrom hydrogen and (C₁ -C₄)alkyl, and the phenyl moiety to which the--NHCOC(R²²)(R²³)--Y⁵ -- sidechain is attached may optionally besubstituted with from one to three substituents independently selectedfrom hydrogen, halo, trifluoromethyl, nitro, cyano, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy and (C₁ -C₄)alkanoyl, or any adjacent pair of substituentsmay form, together with the carbons to which they are attached, a benzoring which may optionally be substituted with a substituentindependently selected from halo, (C₁ -C₄)alkyl and (C₁ -C₄)alkoxy; withthe proviso that: (a) when J is ##STR93## G is CH and L is oxygen; and(b) M is not 2-carboxyphenyl; or a pharmaceutically acceptable saltthereof, that is effective in lowering the level of fructose in one ormore of the tissues of a mammal that are affected by diabetes; and (c) apharmaceutically acceptable carrier.
 21. A pharmaceutical compositioncomprising: (a) an amount of a compound of the formula I, as defined inclaim 2, or a pharmaceutically acceptable salt thereof, effective intreating or preventing a diabetic complication such as diabeticneuropathy, diabetic retinopathy, diabetic nephropathy, or diabeticmicroangiopathy or macroangiopathy in a mammal; (b) an amount of acompound of the formula XV, XVI, XVII, XVIII or XIX, as defined in claim20, or a pharmaceutically acceptable salt thereof, effective in treatingor preventing a diabetic complication such as diabetic neuropathy,diabetic retinopathy, diabetic nephropathy or diabetic microangiopathyor macroangiopathy in a mammal; and (c) a pharmaceutically acceptablecarrier.
 22. A pharmaceutical composition according to claim 20, whereinthe compound of formula I, or pharmaceutically acceptable salt thereof,that is employed is a compound wherein R¹ is (C₁ -C₆)alkoxycarbonyl-(C₁-C₆)alkyl, (C₁ -C₆)alkyl--S--(C₁ -C₆)alkyl, (C₁ -C₆)alkyl--SO--(C₁-C₆)alkyl, (C₁ -C₆)alkyl--SO₂ --(C₁ -C₆)alkyl, dihydroxy-(C₁ -C₆)alkyl,aryl, heteroaryl, heteroaryl-(C₁ -C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonylaryl, aryl-(C₁ -C₆)alkyloxy or heteroaryl-(C₁-C₆)alkyloxy, wherein said aryl and the aryl moieties of said aryl-(C₁-C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl, and aryl-(C₁ -C₆)alkyloxy areindependently selected from phenyl and naphthyl, and wherein saidheteroaryl and the heteroaryl moieties of said heteroaryl-(C₁ -C₆)alkyland heteroaryl-(C₁ -C₆)alkyloxy are independently selected from whereinthe aryl moiety is selected from phenyl and naphthyl, heteroarylselected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyl, andwherein said aryl and heteroaryl and the aryl and heteroaryl moieties ofsaid heteroaryl-(C₁ -C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonylaryl, aryl-(C₁ -C₆)alkyloxy and heteroaryl-(C₁-C₆)alkyloxy may optionally be substituted with one or more substituentsindependently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, hydroxy-(C₁ -C₆)alkyl and trifluoromethyl.
 23. Apharmaceutical composition according to claim 21, wherein the compoundof formula I, or pharmaceutically acceptable salt thereof, that isemployed, is a compound wherein R¹ is (C₁ -C₆)alkoxycarbonyl-(C₁-C₆)alkyl, (C₁ -C₆)alkyl--S--(C₁ -C₆)alkyl, (C₁ -C₆)alkyl --SO--(C₁-C₆)alkyl, (C₁ -C₆)alkyl--SO₂ --(C₁ -C₆)alkyl, dihydroxy-(C₁ -C₆)alkyl,aryl, heteroaryl, heteroaryl-(C₁ -C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonylaryl, aryl-(C₁ -C₆)alkyloxy or heteroaryl-(C₁-C₆)alkyloxy, wherein said aryl and the aryl moieties of said aryl-(C₁-C₆)alkyl, (C₁ -C₆)alkoxycarbonylaryl, and aryl-(C₁ -C₆)alkyloxy areindependently selected from phenyl and naphthyl, and wherein saidheteroaryl and the heteroaryl moieties of said heteroaryl-(C₁ -C₆)alkyland heteroaryl-(C₁ -C₆)alkyloxy are independently selected from whereinthe aryl moiety is selected from phenyl and naphthyl, heteroarylselected from pyridyl, furyl, tetrahydrofuryl, thienyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, oxazolyl and benzothiazolyl, andwherein said aryl and heteroaryl and the aryl and heteroaryl moieties ofsaid heteroaryl-(C₁ -C₆)alkyl, aryl-(C₁ -C₆)alkyl, (C₁-C₆)alkoxycarbonylaryl, aryl-(C₁ -C₆)alkyloxy and heteroaryl-(C₁-C₆)alkyloxy may optionally be substituted with one or more substituentsindependently selected from chloro, bromo, (C₁ -C₆)alkyl, (C₁-C₆)alkoxy, --S--(C₁ -C₆)alkyl, --SO--(C₁ -C₆)alkyl, --SO₂ --(C₁-C₆)alkyl, hydroxy-(C₁ -C₆)alkyl and trifluoromethyl.
 24. Apharmaceutical composition for treating or preventing a diabeticcomplication that can be treated or prevented by inhibiting the enzymesorbitol dehydrogenase in a mammal, comprising a sorbitol dehydrogenaseinhibiting effective amount of a sorbitol dehydrogenase inhibitor or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 25. A pharmaceutical composition for treating orpreventing a diabetic complication that can be treated or prevented byinhibiting the enzyme sorbitol dehydrogenase in a mammal, comprising:a)a sorbitol dehydrogenase inhibitor or a pharmaceutically acceptable saltthereof; and b) an aldose reductase inhibitor or a pharmaceuticallyacceptable salt thereof; and c) a pharmaceutically acceptable carrier;wherein the amounts of the active compounds are such that thecombination is effective in treating or preventing such disorder orcondition.
 26. A method for treating or preventing a diabeticcomplication that can be treated or prevented by inhibiting the enzymesorbitol dehydrogenase in a mammal, comprising administering to saidmammal requiring such treatment or prevention a sorbitol dehydrogenaseinhibiting effective amount of a sorbitol dehydrogenase inhibitor or apharmaceutically acceptable salt thereof.
 27. A method for treating orpreventing a diabetic complication that can be treated or prevented byinhibiting the enzyme sorbitol dehydrogenase in a mammal, comprisingadministering to said mammal requiring such treatment or prevention:a) asorbitol dehydrogenase inhibiting effective amount of a sorbitoldehydrogenase inhibitor or a pharmaceutically acceptable salt thereof;and b) an aldose reductase inhibiting effective amount of an aldosereductase inhibitor or a pharmaceutically acceptable salt thereof.